1-17027878-GGAAGAAGAAGAA-GGAAGAAGAA

Position:

• chr1-17027878-GGAAGAAGAAGAA-GGAAGAAGAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_003000.3(SDHB):​c.424-16_424-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,348,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (0 hom.)
• Consequence: SDHB NM_003000.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-17027878-GGAA-G is Benign according to our data. Variant chr1-17027878-GGAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 811269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17027878-GGAA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00296 (3540/1196786) while in subpopulation AFR AF= 0.0037 (104/28082). AF 95% confidence interval is 0.00313. There are 0 homozygotes in gnomad4_exome. There are 1758 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.424-16_424-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.370-16_370-14del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.424-16_424-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003000.3	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151536 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00605 AC: 1348 AN: 222768 Hom.: 0 AF XY: 0.00632 AC XY: 763 AN XY: 120738

Gnomad AFR exome AF: 0.00656

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00158

Gnomad EAS exome AF: 0.00773

Gnomad SAS exome AF: 0.00482

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00296 AC: 3540 AN: 1196786 Hom.: 0 AF XY: 0.00290 AC XY: 1758 AN XY: 606708

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.00276

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00471

Gnomad4 NFE exome AF: 0.00297

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.000152 AC: 23 AN: 151652 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74074

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 22, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs34261028; hg19: chr1-17354373;