rs121918658

Variant names:

• chr9-133352074-A-C
• rs121918658
• NM_003172.4:c.820T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-133352074-A-C
• chr9-133352074-A-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_003172.4(SURF1):​c.820T>G​(p.Tyr274Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y274C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.67
• Publications: 9 publications found

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]

SURF1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 25 pathogenic changes around while only 9 benign (74%) in NM_003172.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133352073-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2177217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.68006 (below the threshold of 3.09). Trascript score misZ: -1.3185 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 9-133352074-A-C is Pathogenic according to our data. Variant chr9-133352074-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12766.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.820T>G	p.Tyr274Asp	missense_variant	Exon 8 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.493T>G	p.Tyr165Asp	missense_variant	Exon 7 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.820T>G	p.Tyr274Asp	missense_variant	Exon 8 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.493T>G	p.Tyr165Asp	missense_variant	Exon 7 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.730T>G		non_coding_transcript_exon_variant	Exon 7 of 8	5
SURF1	ENST00000495952.5	n.810T>G		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Dec 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with a frameshift variant on the opposite allele (in trans) in a patient with Leigh syndrome in the published literature (PMID: 10647889); Published functional studies using a yeast model system demonstrate that this variant has damaging effect on cytochrome c oxidase assembly (PMID: 21470975); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11955926, 11317352, 10647889, 21470975) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	H;.
PhyloP100		8.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.3	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.96		Loss of sheet (P = 0.0457);.;
MVP		0.97
MPC		0.24
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.99
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121918658; hg19: chr9-136218929;