rs6690934

Positions:

• chr1-17046127-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003000.3(SDHB):​c.73-1239A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 151,858 control chromosomes in the GnomAD database, including 15,139 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (15139 hom., cov: 32)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• 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.73-1239A>G		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.73-1239A>G		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.73-1239A>G		intron_variant		1	NM_003000.3	ENSP00000364649	P1
SDHB	ENST00000463045.3	c.-99-1239A>G		intron_variant		3		ENSP00000481376
SDHB	ENST00000466613.2	n.85-1239A>G		intron_variant, non_coding_transcript_variant		2
SDHB	ENST00000485515.5	n.61-1239A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64035 AN: 151740 Hom.: 15137 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.442

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.422 AC: 64038 AN: 151858 Hom.: 15139 Cov.: 32 AF XY: 0.419 AC XY: 31075 AN XY: 74202

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.437

Alfa AF: 0.477 Hom.: 2274

Bravo AF: 0.410

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.18
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6690934; hg19: chr1-17372622;