rs1060503390

Variant names:

• chr11-61437745-C-A
• rs1060503390
• NM_017841.4:c.157C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61437745-C-A
• chr11-61437745-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017841.4(SDHAF2):​c.157C>A​(p.Pro53Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P53S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.95
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.157C>A	p.Pro53Thr	missense_variant	Exon 2 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.157C>A	p.Pro53Thr	missense_variant	Exon 2 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.157C>A	p.Pro53Thr	missense_variant	Exon 2 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:2

Aug 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with threonine at codon 53 of the SDHAF2 protein (p.Pro53Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SDHAF2-related conditions. This variant is not present in population databases (ExAC no frequency). -

May 31, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P53T variant (also known as c.157C>A), located in coding exon 2 of the SDHAF2 gene, results from a C to A substitution at nucleotide position 157. The proline at codon 53 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.4	.;M;.;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.1	D;D;.;.;D
REVEL	Uncertain	0.48
Sift	Benign	0.041	D;D;.;.;T
Sift4G	Uncertain	0.051	T;T;T;T;T
Polyphen		0.64	.;P;.;.;.
Vest4		0.72, 0.77, 0.73, 0.86
MutPred		0.31		Loss of catalytic residue at P53 (P = 5e-04);Loss of catalytic residue at P53 (P = 5e-04);Loss of catalytic residue at P53 (P = 5e-04);Loss of catalytic residue at P53 (P = 5e-04);Loss of catalytic residue at P53 (P = 5e-04);
MVP		0.60
MPC		0.31
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.67
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs1060503390; hg19: chr11-61205217;