rs978528

chr1-17023303-C-T

Variant summary

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

The NM_003000.3(SDHB):c.643-573G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 188,366 control chromosomes in the GnomAD database, including 65,808 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 0.82 (51869 hom., cov: 33)
  • Exomes 𝑓: 0.87 (13939 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.643-573G>A		intron_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.589-573G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.643-573G>A		intron_variant		1	NM_003000.3	P1
SDHB	ENST00000463045.3	c.472-573G>A		intron_variant		3
SDHB	ENST00000491274.6	c.601-573G>A		intron_variant		5
SDHB	ENST00000485515.5	n.577-573G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124732 AN: 152070 Hom.: 51862 Cov.: 33

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.882

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.900

Gnomad OTH AF: 0.836

GnomAD4 exome AF: 0.874 AC: 31623 AN: 36178 Hom.: 13939 AF XY: 0.879 AC XY: 16520 AN XY: 18786

Gnomad4 AFR exome AF: 0.656

Gnomad4 AMR exome AF: 0.856

Gnomad4 ASJ exome AF: 0.831

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.900

Gnomad4 FIN exome AF: 0.862

Gnomad4 NFE exome AF: 0.901

Gnomad4 OTH exome AF: 0.877

GnomAD4 genome AF: 0.820 AC: 124781 AN: 152188 Hom.: 51869 Cov.: 33 AF XY: 0.818 AC XY: 60869 AN XY: 74408

Gnomad4 AFR AF: 0.669

Gnomad4 AMR AF: 0.842

Gnomad4 ASJ AF: 0.822

Gnomad4 EAS AF: 0.744

Gnomad4 SAS AF: 0.882

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.900

Gnomad4 OTH AF: 0.833

Alfa AF: 0.884 Hom.: 76439

Bravo AF: 0.810

Asia WGS AF: 0.768 AC: 2672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.077
Dann	Benign	0.66

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: rs978528; hg19: chr1-17349798;