chr9-133351918-C-G

Variant names:

• chr9-133351918-C-G
• rs782746186
• NM_003172.4:c.898G>C

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>C​(p.Val300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 17 pathogenic changes around while only 2 benign (89%) in NM_003172.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052528054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.898G>C	p.Val300Leu	missense_variant	Exon 9 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.571G>C	p.Val191Leu	missense_variant	Exon 8 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.898G>C	p.Val300Leu	missense_variant	Exon 9 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.571G>C	p.Val191Leu	missense_variant	Exon 8 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.808G>C		non_coding_transcript_exon_variant	Exon 8 of 8	5
SURF1	ENST00000495952.5	n.888G>C		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250132 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461308 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.0060
DANN	Benign	0.81
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.22	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.22
Sift	Benign	0.21	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.36		Loss of MoRF binding (P = 0.0929);.;
MVP		0.13
MPC		0.024
ClinPred		0.050	T
GERP RS		-7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.59

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: rs782746186; hg19: chr9-136218773;