rs774508076

chr11-61437753-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_017841.4(SDHAF2):c.165G>A(p.Trp55Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 8.81

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-61437753-G-A is Pathogenic according to our data. Variant chr11-61437753-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384524.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHAF2	NM_017841.4	c.165G>A	p.Trp55Ter	stop_gained	2/4	ENST00000301761.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHAF2	ENST00000301761.7	c.165G>A	p.Trp55Ter	stop_gained	2/4	1	NM_017841.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251250 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135784

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 02, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 384524). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. This variant is present in population databases (rs774508076, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Trp55*) in the SDHAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHAF2 are known to be pathogenic (PMID: 22241717, 26096992). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant changes 1 nucleotide in exon 2 of the SDHAF2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with SDHAF2-like disorders, but a different variant with the same protein consequence (c.164G>A, p.Trp55*) has been observed in an individual with a bilateral carotid body tumor (PMID: 36597280). This variant has been identified in 5/251250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in SDHAF2 are an expected mechanism of disease (PMID: 22241717, 26096992). Based on the available evidence, this variant is classified as Pathogenic. -

Paragangliomas 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 22, 2023

This variant changes 1 nucleotide in exon 2 of the SDHAF2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with SDHAF2-like disorders, but a different variant with the same protein consequence (c.164G>A, p.Trp55*) has been observed in an individual with a bilateral carotid body tumor (PMID: 36597280). This variant has been identified in 5/251250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in SDHAF2 are an expected mechanism of disease (PMID: 22241717, 26096992). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2016

The W55X variant in the SDHAF2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W55X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W55X variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2023

The p.W55* pathogenic mutation (also known as c.165G>A), located in coding exon 2 of the SDHAF2 gene, results from a G to A substitution at nucleotide position 165. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. A similar variant resulting in the same protein truncation (c.164G>A, p.W55*) has been reported in a Japanese patient who was diagnosed with bilateral paragangliomas at age 73 (Yoshihama K et al. Clin Genet, 2023 Jan;:). This c.165G>A variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 27, 2017

The p.Trp55X variant in SDHAF2 has not been previously reported in individuals w ith SDHAF2-associated hereditary paraganglioma-pheochromocytoma syndromes but ha s been identified in 3/66432 European chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs774508076). This nonsense v ariant leads to a premature termination codon at position 55, which is predicted to lead to a truncated or absent protein. Although this variant is expected to severely impact the protein, the spectrum of disease-causing variants is not we ll defined for SDHAF2. In summary, the clinical significance of the p.Trp55X var iant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.81, 0.82, 0.77, 0.83
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs774508076; hg19: chr11-61205225;