9-133351918-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_003172.4(SURF1):c.898G>A(p.Val300Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V300V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.10

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 Uncertain_significance. Variant got 0 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046308964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.898G>A	p.Val300Met	missense_variant	9/9	ENST00000371974.8
SURF1	NM_001280787.1	c.571G>A	p.Val191Met	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.898G>A	p.Val300Met	missense_variant	9/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.571G>A	p.Val191Met	missense_variant	8/8	1
SURF1	ENST00000437995.1	n.808G>A		non_coding_transcript_exon_variant	8/8	5
SURF1	ENST00000495952.5	n.888G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461308 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726870

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2018

- -

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: 985138). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 300 of the SURF1 protein (p.Val300Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	0.012
Dann	Benign	0.64
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.60	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N;.
REVEL	Benign	0.21
Sift	Benign	0.19	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.0	B;.
Vest4		0.074
MutPred		0.42		Gain of disorder (P = 0.1085);.;
MVP		0.13
MPC		0.025
ClinPred		0.19	T
GERP RS		-7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782746186; hg19: chr9-136218773;