chr1-17018721-CT-C

Position:

• chr1-17018721-CT-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_003000.3(SDHB):​c.*159del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 532,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (0 hom.)
• Consequence: SDHB NM_003000.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.11

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-17018721-CT-C is Benign according to our data. Variant chr1-17018721-CT-C is described in ClinVar as [Benign]. Clinvar id is 1292226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00813 (3121/384010) while in subpopulation NFE AF= 0.00839 (1982/236306). AF 95% confidence interval is 0.00808. There are 0 homozygotes in gnomad4_exome. There are 1727 alleles in male gnomad4_exome subpopulation. Median coverage is 4. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.*159del		3_prime_UTR_variant	8/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1			downstream_gene_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.*159del		3_prime_UTR_variant	8/8	1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 49 AN: 148400 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000284

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00813 AC: 3121 AN: 384010 Hom.: 0 Cov.: 4 AF XY: 0.00827 AC XY: 1727 AN XY: 208798

Gnomad4 AFR exome AF: 0.00834

Gnomad4 AMR exome AF: 0.00824

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.00721

Gnomad4 SAS exome AF: 0.00541

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.00839

Gnomad4 OTH exome AF: 0.00816

GnomAD4 genome AF: 0.000330 AC: 49 AN: 148400 Hom.: 0 Cov.: 32 AF XY: 0.000415 AC XY: 30 AN XY: 72326

Gnomad4 AFR AF: 0.0000495

Gnomad4 AMR AF: 0.0000674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000284

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000378 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs532333715; hg19: chr1-17345216;