rs1456129845

Variant names:

• chr11-61438095-A-AT
• rs1456129845
• NM_017841.4:c.355dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PVS1_Strong PP5 BS2

The NM_017841.4(SDHAF2):​c.355dupT​(p.Tyr119LeufsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 7.27
• Publications: 1 publications found

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]

SDHAF2 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma/paraganglioma syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000256591 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 11-61438095-A-AT is Pathogenic according to our data. Variant chr11-61438095-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403423.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.355dupT	p.Tyr119LeufsTer8	frameshift_variant	Exon 3 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.355dupT	p.Tyr119LeufsTer8	frameshift_variant	Exon 3 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.355dupT	p.Tyr119LeufsTer20	frameshift_variant	Exon 3 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251486 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460914 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726842

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111124

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.0000483 AC: 2 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:2 Uncertain:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr119Leufs*8) in the SDHAF2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the SDHAF2 protein. This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with a right carotid body paranglioma (PMID: 22241717). ClinVar contains an entry for this variant (Variation ID: 403423). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 3 of the SDHAF2 gene, creating a frameshift and premature translation stop signal. This variant is expected to escape nonsense-mediated decay but result in a non-functional protein product. This variant impacts the C-terminal 48 amino acids. Functional studies have shown that a deletion of the C-terminal 15 amino acids of SDHAF2 abolished SDHA-SDHAF2 interaction and SDHA flavination (PMID: 32887801). This variant has been reported in an individual affected with a right carotid body paraganglioma (PMID: 22241717). This variant has been identified in 2/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Apr 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 3 of the SDHAF2 gene, creating a frameshift and premature translation stop signal. This variant is expected to escape nonsense-mediated decay but result in a non-functional protein product. This variant impacts the C-terminal 48 amino acids. Functional studies have shown that a deletion of the C-terminal 15 amino acids of SDHAF2 abolished SDHA-SDHAF2 interaction and SDHA flavination (PMID: 32887801). This variant has been reported in an individual affected with a right carotid body paraganglioma (PMID: 22241717). This variant has been identified in 2/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHAF2: PVS1:Strong, PM2, PS4:Moderate -

Sep 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 48 amino acids are replaced with 7 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25394176, 22241717, 21752896, 31687641, 19628817, 23062074, 32887801) -

SDHAF2-related disorder Pathogenic:1

Jan 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHAF2 c.355dupT variant is predicted to result in a frameshift and premature protein termination (p.Tyr119Leufs*8). This variant has been reported in patients with paraganglioma/pheochromocytoma tumors (Table S1 in Evenepoel L et al 2014. PubMed ID: 25394176; reported as c.357_358insT Piccini et al. 2012. PubMed ID: 22241717). This variant occurs in the 2nd to last exon and may not result in non-sense mediated decay. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Frameshift variants in SDHAF2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Pheochromocytoma/paraganglioma syndrome 2 Pathogenic:1

Jun 13, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.355dupT (p.Y119Lfs*8) alteration, located in exon 3 (coding exon 3) of the SDHAF2 gene, consists of a duplication of T at position 355, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration occurs at the 3' terminus of theSDHAF2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 48 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/282866) total alleles studied. The highest observed frequency was 0.004% (1/24968) of African alleles. This variant (reported as c.357_358insT in one study) has been detected in two unrelated individuals with a paraganglioma (Piccini, 2012; Evenepoel, 2015). Based on internal structural analysis, this mutation removes a large portion of the SDHAF2-SDHA interface and is likely to disrupt protein function and stability (Hao, 2009; Eletsky, 2012; Sharma, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

not specified Uncertain:1

Jun 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF not established disease mechanism for this gene -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=2/198	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1456129845; hg19: chr11-61205567;