chr11-61430148-T-C

Position:

• chr11-61430148-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_017841.4(SDHAF2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,018 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.34

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.2T>C	p.Met1?	start_lost	1/4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.2T>C	p.Met1?	start_lost	1/4	1	NM_017841.4	ENSP00000301761	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461842 Hom.: 0 Cov.: 31 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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2023	The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the SDHAF2 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 12 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 411609). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SDHAF2 mRNA. The next in-frame methionine is located at codon 13. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;T;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	0.99	N;N
PROVEAN	Benign	-0.76	N;N;.;.;.;N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;.;D;D;D
Polyphen		0.93	.;P;.;.;.;.
Vest4		0.93, 0.93, 0.91, 0.93, 0.91
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);
MVP		0.62
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.47

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: rs1060503392; hg19: chr11-61197620;