1-17032891-T-C

Position:

• chr1-17032891-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003000.3(SDHB):​c.286+169A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 677,548 control chromosomes in the GnomAD database, including 81,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15162 hom., cov: 32)
  • Exomes 𝑓: 0.50 (66403 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-17032891-T-C is Benign according to our data. Variant chr1-17032891-T-C is described in ClinVar as [Benign]. Clinvar id is 1234802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.286+169A>G		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.286+169A>G		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.286+169A>G		intron_variant		1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64082 AN: 151968 Hom.: 15159 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.495 AC: 260231 AN: 525460 Hom.: 66403 Cov.: 4 AF XY: 0.495 AC XY: 139967 AN XY: 282562

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.485

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.537

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.421 AC: 64087 AN: 152088 Hom.: 15162 Cov.: 32 AF XY: 0.418 AC XY: 31089 AN XY: 74338

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.300

Gnomad4 SAS AF: 0.449

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.438

Alfa AF: 0.503 Hom.: 18352

Bravo AF: 0.410

Asia WGS AF: 0.355 AC: 1238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.4
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs10887990; hg19: chr1-17359386;