1-17028580-A-T

Position:

chr1-17028580-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003000.3(SDHB):c.423+20T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,868 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 29 hom. )

Consequence

SDHB
NM_003000.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:15

Conservation

PhyloP100: -0.0320

Variant links:

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

SDHB links:

SDHB (HGNC:):

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-17028580-A-T is Benign according to our data. Variant chr1-17028580-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=5}. Variant chr1-17028580-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00192 (292/152330) while in subpopulation SAS AF= 0.00745 (36/4830). AF 95% confidence interval is 0.00553. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 29 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.423+20T>A		intron_variant		ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 linkuse as main transcript	c.369+74T>A		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.423+20T>A		intron_variant		1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00314

AC:

789

AN:

251332

Hom.:

AF XY:

0.00361

AC XY:

490

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00964

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00332

AC:

4852

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

2604

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00620

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0100

Gnomad4 FIN exome

AF:

0.000507

Gnomad4 NFE exome

AF:

0.00309

Gnomad4 OTH exome

AF:

0.00376

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152330

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00745

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00253

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00191

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SDHB c.423+20T>A variant was identified in the in heterozygous state in the tumour of one patient with pheochromocytoma (Pantaleo_2014_23612575) and in the tumours of two patients with Carney Triad (association of paragangliomas, pulmonary chondromas, and gastrointestinal stromal tumors with variety of other lesions including pheochromocytomas and adrenocortical tumors) who were also found to have SDHD c.388insG variants (Szarek_2015_25808178). The variant was also identified in dbSNP (ID: rs190139590) as â€šÃ„ÃºWith Likely pathogenic alleleâ€šÃ„Ã¹. The variant was found in ClinVar with conflicting interpretations of pathogenicity as it was classified as likely benign by Children's Mercy Hospital and Clinics, GeneDx, and Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine, benign by Prevention Genetics and Invitae, but was classified as likely pathogenic by Integrated Genetics/Laboratory Corporation of America. The variant was found in LOVD 3.0 where it was reported as likely benign. The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 847 of 282734 chromosomes (8 homozygous) at a frequency of 0.002996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 295 of 30614 chromosomes (freq: 0.009636), Ashkenazi Jewish in 69 of 10370 chromosomes (freq: 0.006654), Other in 28 of 7224 chromosomes (freq: 0.003876), European (Non-Finnish) in 370 of 129148 chromosomes (freq: 0.002865), Latino in 71 of 35438 chromosomes (freq: 0.002003), European (Finnish) in 10 of 25020 chromosomes (freq: 0.0004), African in 3 of 24966 chromosomes (freq: 0.00012) and East African in 1 of 19954 chromosomes (freq: 0.00005). Pathogenic variants in SDHB have been associated with Cowden Syndrome, an autosomal dominant condition with an estimated prevalence of 1 in 200 000 and Paragangliomas, an autosomal dominant condition with an estimated prevalence of 1 in 1 000 000. The observed allele frequency is therefore higher than would be expected for the disorder. Three in silico splicing programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE) predict a greater than 10% change in splicing which would lead to the creation of a new 3' splice site, however MutationTaster predicts that this variant is a polymorphism. This information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Pantaleo, Maria A., et al. "Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST." European Journal of Human Genetics 22.1 (2014): 32. Szarek, Eva, et al. "Carney triad, SDH-deficient tumors, and Sdhb+/â€šÃ Ã mice share abnormal mitochondria." Endocrine-related cancer 22.3 (2015): 345-352. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SDHB: BS2 -

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified in HGMD as DM. It has been seen in 2 patients with pheochromocytomas and one with GIST. It is present with a MaxMAF of 0.89% in ExAC (high for disease frequency - 0.8/100,000 person-years). It is classified in ClinVar with 1 star as benign/likely benign by Invitae, GeneDx, Prevention genetics and as likely path by LabCorp (in 2011). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2017	Variant summary: The SDHB c.423+20T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and 4/5 splice prediction tools predict changes of a cryptic splicing site. ESEfinder predicts changes of RNA splicing enhancer sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 374/121320 control chromosomes (4 homozygotes) at a frequency of 0.0030828, which is approximately 3523 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. This variant has been reported in the affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 2015	The c.423+20T>A intronic variant results from a T to A substitution 20 nucleotides after coding exon 4 in the SDHB gene. In one study, this alteration was reported in 2 apparently unrelated individuals with an adrenal pheochromocytoma diagnosed prior to age 50 (Srirangalingam U et al. Clin Endocrinol. 2008 Oct;69(4):587-96). Neither of these probands had an identifiable VHL mutation; however, other susceptibility genes were not assessed. Authors classified c.423+20T>A as a mutation, but cautioned that further studies were needed to confirm pathogenicity. This variant was previously reported in the SNPDatabase as rs190139590. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.22% (28/13006), having been observed in 0.02% (1/4406) of African American alleles, and in 0.31% (27/8600) of European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 1 of 178 (0.56%) British chromosomes studied. To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 6100 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a cryptic splice acceptor site in close proximity to the native donor site; however, direct evidence is unavailable. Since supporting evidence for this variant is conflicting at this time, the clinical significance of c.423+20T>A remains unclear. -

Paragangliomas 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 21, 2018

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Gastrointestinal stromal tumor

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over