9-133356606-C-A

Variant names:

• chr9-133356606-C-A
• rs1443228220
• NM_017503.5:c.14C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017503.5(SURF2):​c.14C>A​(p.Pro5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,372,696 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SURF2 NM_017503.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.437

Genes affected

SURF2 (HGNC:11475): (surfeit 2) This gene shares a bidirectional promoter with surfeit 1 (SURF1; GeneID: 6834), which is located on the opposite strand. It encodes a conserved protein that is expressed in a variety of tissues. [provided by RefSeq, Jul 2013]

SURF1 (HGNC:11474): (SURF1 cytochrome c oxidase assembly factor) This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
SURF2	NM_017503.5	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 6	ENST00000371964.5	NP_059973.4
SURF2	NM_001278928.2	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 6		NP_001265857.1
SURF1	NM_003172.4	c.-153G>T		upstream_gene_variant		ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.-428G>T		upstream_gene_variant			NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF2	ENST00000371964.5	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 6	1	NM_017503.5	ENSP00000361032.4
SURF1	ENST00000371974.8	c.-153G>T		upstream_gene_variant		1	NM_003172.4	ENSP00000361042.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1372696 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 677420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000293

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.035	N
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.098
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0040	D
Vest4		0.17
MutPred		0.83		Loss of phosphorylation at S2 (P = 0.1374);
MVP		0.45
MPC		0.34
ClinPred		0.99	D
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.39

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: rs1443228220; hg19: chr9-136223482;