rs147312193

chr9-133351933-G-Achr9-133351933-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003172.4(SURF1):c.883C>T(p.Arg295Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000791 in 1,613,880 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.81

Genes affected

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 -18 ACMG points.

• PM1: In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 46 pathogenic changes around while only 10 benign (82%) in NM_003172.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.005872637).
• BP6: Variant 9-133351933-G-A is Benign according to our data. Variant chr9-133351933-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133351933-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00419 (638/152336) while in subpopulation AFR AF= 0.0148 (615/41570). AF 95% confidence interval is 0.0138. There are 8 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.883C>T	p.Arg295Cys	missense_variant	9/9	ENST00000371974.8
SURF1	NM_001280787.1	c.556C>T	p.Arg186Cys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.883C>T	p.Arg295Cys	missense_variant	9/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.556C>T	p.Arg186Cys	missense_variant	8/8	1
SURF1	ENST00000437995.1	n.793C>T		non_coding_transcript_exon_variant	8/8	5
SURF1	ENST00000495952.5	n.873C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 638 AN: 152218 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 250594 Hom.: 3 AF XY: 0.000752 AC XY: 102 AN XY: 135566

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000437 AC: 639 AN: 1461544 Hom.: 6 Cov.: 32 AF XY: 0.000338 AC XY: 246 AN XY: 727016

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152336 Hom.: 8 Cov.: 33 AF XY: 0.00395 AC XY: 294 AN XY: 74506

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.00454

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 17, 2017

Variant summary: The c.883C>T (p.Arg295Cys) in SURF1 gene is a missense change that involves a non-conserved nucleotide and 2/4 in silico tools predict benign outcome. The variant is located outside of any known functional domain and no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.001516 (173/114150 chrs tested), predominantly in individuals of African descent (0.01761; 166/9424 chrs tested, including 2 homozygotes. The observed frequency exceed the maximum expected allele frequency for a pathogenic variant of 0.00176. The variant is present in a control population dataset of gnomAD at a frequency of 0.001517 (428/282054 chrs), mainly in individuals of African origin: 0.015 (406/25770 chrs, including 7 homozygotes). This data suggest that the variant of interest may be an ethnic-specific polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports or cited by reputable databases/clinical laboratories. Taking together, the variant was classified as Likely Benign. -

SURF1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	16
Dann	Benign	0.90
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.50	N
MetaRNN	Benign	0.0059	T;T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.40	B;.
Vest4		0.28
MVP		0.83
MPC		0.030
ClinPred		0.049	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.78

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: rs147312193; hg19: chr9-136218788;