9-133356665-C-T

Variant names:

• chr9-133356665-C-T
• rs143037947
• NM_017503.5:c.73C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017503.5(SURF2):​c.73C>T​(p.Arg25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,516,852 control chromosomes in the GnomAD database, including 611 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (99 hom., cov: 32)
  • Exomes 𝑓: 0.021 (512 hom.)
• Consequence: SURF2 NM_017503.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.20

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015997291).
• BP6: Variant 9-133356665-C-T is Benign according to our data. Variant chr9-133356665-C-T is described in ClinVar as [Benign]. Clinvar id is 1292593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133356665-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF2	NM_017503.5	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 6	ENST00000371964.5	NP_059973.4
SURF2	NM_001278928.2	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 6		NP_001265857.1
SURF1	NM_003172.4	c.-212G>A		upstream_gene_variant		ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.-487G>A		upstream_gene_variant			NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF2	ENST00000371964.5	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 6	1	NM_017503.5	ENSP00000361032.4
SURF1	ENST00000371974.8	c.-212G>A		upstream_gene_variant		1	NM_003172.4	ENSP00000361042.3

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3105 AN: 151938 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00491

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0279

GnomAD3 exomes AF: 0.0440 AC: 4894 AN: 111340 Hom.: 217 AF XY: 0.0396 AC XY: 2451 AN XY: 61926

Gnomad AFR exome AF: 0.00569

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.000501

Gnomad SAS exome AF: 0.0511

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0206 AC: 28147 AN: 1364806 Hom.: 512 Cov.: 38 AF XY: 0.0211 AC XY: 14229 AN XY: 673136

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0363

Gnomad4 EAS exome AF: 0.000296

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0205 AC: 3114 AN: 152046 Hom.: 99 Cov.: 32 AF XY: 0.0222 AC XY: 1651 AN XY: 74332

Gnomad4 AFR AF: 0.00492

Gnomad4 AMR AF: 0.0831

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0276

Alfa AF: 0.0184 Hom.: 6

Bravo AF: 0.0261

ESP6500AA AF: 0.00286 AC: 8

ESP6500EA AF: 0.0120 AC: 79

ExAC AF: 0.0164 AC: 1473

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.9
DANN	Benign	0.93
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0060	N
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.017
Sift	Benign	0.090	T
Sift4G	Benign	0.083	T
Vest4		0.049
MPC		0.079
ClinPred		0.0051	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.34

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: rs143037947; hg19: chr9-136223541;