1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAA

Position:

chr1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1

The NM_003000.3(SDHB):c.424-14_424-13insTTC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0008 in 1,377,890 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

SDHB
NM_003000.3 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 0.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 1-17027878-G-GGAA is Benign according to our data. Variant chr1-17027878-G-GGAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44644.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=5}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00119 (180/151666) while in subpopulation SAS AF= 0.0025 (12/4804). AF 95% confidence interval is 0.00144. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.424-14_424-13insTTC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375499.8
SDHB	NM_001407361.1 linkuse as main transcript	c.370-14_370-13insTTC		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.424-14_424-13insTTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003000.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

151550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000727

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00127

AC:

284

AN:

222768

Hom.:

AF XY:

0.00128

AC XY:

154

AN XY:

120738

show subpopulations

Gnomad AFR exome

AF:

0.000838

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.000317

Gnomad EAS exome

AF:

0.000503

Gnomad SAS exome

AF:

0.00205

Gnomad FIN exome

AF:

0.000111

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.000752

AC:

922

AN:

1226224

Hom.:

Cov.:

AF XY:

0.000804

AC XY:

500

AN XY:

622142

show subpopulations

Gnomad4 AFR exome

AF:

0.000519

Gnomad4 AMR exome

AF:

0.00158

Gnomad4 ASJ exome

AF:

0.000203

Gnomad4 EAS exome

AF:

0.000207

Gnomad4 SAS exome

AF:

0.00166

Gnomad4 FIN exome

AF:

0.000211

Gnomad4 NFE exome

AF:

0.000688

Gnomad4 OTH exome

AF:

0.000913

GnomAD4 genome

AF:

0.00119

AC:

180

AN:

151666

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74084

show subpopulations

Gnomad4 AFR

AF:

0.000725

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00250

Gnomad4 FIN

AF:

0.000191

Gnomad4 NFE

AF:

0.00146

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2012	Variant classified as Uncertain Significance - Favor Benign. The 424-16_424-14du pTTC variant in SDHB has not been previously identified by our laboratory or in the literature. This variant is located in the 3' splice region. Computational t ools do not suggest an impact to splicing. However, this information is not pred ictive enough to rule out pathogenicity. In summary, although this data supports that the 424-16_424-14dupTTC variant may be benign, additional studies are need ed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	SDHB: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2022	- -

Pheochromocytoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Carney-Stratakis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Paragangliomas 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 21, 2022

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 14, 2020

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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