1-17027878-GGAAGAAGAAGAA-GGAAGAA

Position:

chr1-17027878-GGAAGAAGAAGAA-GGAAGAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003000.3(SDHB):c.424-19_424-14del 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 0.00229 in 1,377,784 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 11 hom. )

Consequence

SDHB
NM_003000.3 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 2.43

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 1-17027878-GGAAGAA-G is Benign according to our data. Variant chr1-17027878-GGAAGAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=2}. Variant chr1-17027878-GGAAGAA-G is described in Lovd as [Likely_benign]. Variant chr1-17027878-GGAAGAA-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00222 (337/151668) while in subpopulation AMR AF= 0.00382 (58/15188). AF 95% confidence interval is 0.00303. There are 0 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.424-19_424-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375499.8
SDHB	NM_001407361.1 linkuse as main transcript	c.370-19_370-14del		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.424-19_424-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003000.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

337

AN:

151552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00382

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.000574

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00224

AC:

500

AN:

222768

Hom.:

AF XY:

0.00238

AC XY:

287

AN XY:

120738

show subpopulations

Gnomad AFR exome

AF:

0.000978

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00433

Gnomad EAS exome

AF:

0.000440

Gnomad SAS exome

AF:

0.00230

Gnomad FIN exome

AF:

0.000444

Gnomad NFE exome

AF:

0.00301

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.00229

AC:

2813

AN:

1226116

Hom.:

AF XY:

0.00238

AC XY:

1483

AN XY:

622084

show subpopulations

Gnomad4 AFR exome

AF:

0.000795

Gnomad4 AMR exome

AF:

0.00162

Gnomad4 ASJ exome

AF:

0.00488

Gnomad4 EAS exome

AF:

0.000155

Gnomad4 SAS exome

AF:

0.00229

Gnomad4 FIN exome

AF:

0.000538

Gnomad4 NFE exome

AF:

0.00245

Gnomad4 OTH exome

AF:

0.00324

GnomAD4 genome

AF:

0.00222

AC:

337

AN:

151668

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

160

AN XY:

74086

show subpopulations

Gnomad4 AFR

AF:

0.000556

Gnomad4 AMR

AF:

0.00382

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.000574

Gnomad4 NFE

AF:

0.00309

Gnomad4 OTH

AF:

0.00427

Bravo

AF:

0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

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	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Aug 17, 2022

- -

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