NM_003000.3:c.643-573G>A

Variant names:

• chr1-17023303-C-T
• rs978528
• NM_003000.3:c.643-573G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.643-573G>A		intron_variant	Intron 6 of 7	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.589-573G>A		intron_variant	Intron 6 of 7		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.643-573G>A		intron_variant	Intron 6 of 7	1	NM_003000.3	ENSP00000364649.3

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

African (AFR) AF: 0.656 AC: 643 AN: 980

American (AMR) AF: 0.856 AC: 3040 AN: 3552

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 507 AN: 610

East Asian (EAS) AF: 0.741 AC: 2085 AN: 2814

South Asian (SAS) AF: 0.900 AC: 4265 AN: 4740

European-Finnish (FIN) AF: 0.862 AC: 893 AN: 1036

Middle Eastern (MID) AF: 0.886 AC: 78 AN: 88

European-Non Finnish (NFE) AF: 0.901 AC: 18608 AN: 20644

Other (OTH) AF: 0.877 AC: 1504 AN: 1714

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

African (AFR) AF: 0.669 AC: 27753 AN: 41484

American (AMR) AF: 0.842 AC: 12877 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 2852 AN: 3470

East Asian (EAS) AF: 0.744 AC: 3843 AN: 5168

South Asian (SAS) AF: 0.882 AC: 4252 AN: 4822

European-Finnish (FIN) AF: 0.864 AC: 9162 AN: 10606

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.900 AC: 61192 AN: 68020

Other (OTH) AF: 0.833 AC: 1761 AN: 2114

Alfa AF: 0.875 Hom.: 95627

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
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs978528; hg19: chr1-17349798;