11-61430152-GGTGTCTACAGT-G

Variant names:

• chr11-61430152-GGTGTCTACAGT-G
• NM_017841.4:c.9_19delGTCTACAGTGT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PVS1_Strong PM2 PP5_Very_Strong BS2

The NM_017841.4(SDHAF2):​c.9_19delGTCTACAGTGT​(p.Ser4LeufsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.82

Genes affected

SDHAF2 (HGNC:26034): (succinate dehydrogenase complex assembly factor 2) This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

ENSG00000256591 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.982 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-61430152-GGTGTCTACAGT-G is Pathogenic according to our data. Variant chr11-61430152-GGTGTCTACAGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2774506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.9_19delGTCTACAGTGT	p.Ser4LeufsTer31	frameshift_variant	Exon 1 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.9_19delGTCTACAGTGT	p.Ser4LeufsTer31	frameshift_variant	Exon 1 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.9_19delGTCTACAGTGT	p.Ser4LeufsTer31	frameshift_variant	Exon 1 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461848 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 2 Pathogenic:1

Apr 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 11 nucleotides in exon 1 of the SDHAF2 gene, creating a frameshift and premature translation stop signal 31 codons downstream. This variant is expected to result in an absent or non-functional protein product by either nonsense mediated decay or by disrupting the signal presequence required for import into mitochondria. Translation of the frameshift extension is expected to bypass the in-frame methionine at codon 13 making re-initiation from this initiator codon unlikely, and re-initiation further downstream at the methionine at codon 47 would create a protein without the mitochondrial import signal. To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9_19del11 variant, located in coding exon 1 of the SDHAF2 gene, results from a deletion of 11 nucleotides at nucleotide positions 9 to 19, causing a translational frameshift with a predicted alternate stop codon (p.S4Lfs*31). The predicted stop codon occurs in the 5&rsquo; end of theSDHAF2 gene. Premature termination codons in the 5&rsquo; end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 11 nucleotides in exon 1 of the SDHAF2 gene, creating a frameshift and premature translation stop signal 31 codons downstream. This variant is expected to result in an absent or non-functional protein product by either nonsense mediated decay or by disrupting the signal presequence required for import into mitochondria. Translation of the frameshift extension is expected to bypass the in-frame methionine at codon 13 making re-initiation from this initiator codon unlikely, and re-initiation further downstream at the methionine at codon 47 would create a protein without the mitochondrial import signal. To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-61197624;