1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAAGAA

Position:

chr1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAAGAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003000.3(SDHB):c.424-14_424-13insTTCTTC 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 0.0034 in 1,377,998 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 12 hom. )

Consequence

SDHB
NM_003000.3 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

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 Benign. Variant got -16 ACMG points.

BP6

Variant 1-17027878-G-GGAAGAA is Benign according to our data. Variant chr1-17027878-G-GGAAGAA is described in ClinVar as [Likely_benign]. Clinvar id is 36770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00358 (543/151664) while in subpopulation AMR AF= 0.00507 (77/15188). AF 95% confidence interval is 0.00444. There are 4 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.424-14_424-13insTTCTTC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375499.8
SDHB	NM_001407361.1 linkuse as main transcript	c.370-14_370-13insTTCTTC		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_424-13insTTCTTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003000.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

542

AN:

151548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00112

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.00508

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00105

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.00487

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00461

AC:

1028

AN:

222768

Hom.:

AF XY:

0.00486

AC XY:

587

AN XY:

120738

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.000252

Gnomad SAS exome

AF:

0.00191

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00629

Gnomad OTH exome

AF:

0.00765

GnomAD4 exome

AF:

0.00338

AC:

4149

AN:

1226334

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

2232

AN XY:

622194

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00325

Gnomad4 ASJ exome

AF:

0.0121

Gnomad4 EAS exome

AF:

0.000130

Gnomad4 SAS exome

AF:

0.00166

Gnomad4 FIN exome

AF:

0.00194

Gnomad4 NFE exome

AF:

0.00349

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00358

AC:

543

AN:

151664

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

251

AN XY:

74086

show subpopulations

Gnomad4 AFR

AF:

0.00114

Gnomad4 AMR

AF:

0.00507

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.00105

Gnomad4 NFE

AF:

0.00487

Gnomad4 OTH

AF:

0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SDHB: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

Pheochromocytoma

Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

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 20, 2022

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 04, 2021

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 01, 2021

- -

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