9-133352593-C-T

Variant names:

• chr9-133352593-C-T
• rs72619327
• NM_003172.4:c.604G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003172.4(SURF1):​c.604G>A​(p.Asp202Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D202H) has been classified as Likely benign.

• 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: 5.82
• Publications: 19 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003172.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.604G>A	p.Asp202Asn	missense_variant	Exon 7 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.277G>A	p.Asp93Asn	missense_variant	Exon 6 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.604G>A	p.Asp202Asn	missense_variant	Exon 7 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.277G>A	p.Asp93Asn	missense_variant	Exon 6 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.514G>A		non_coding_transcript_exon_variant	Exon 6 of 8	5
SURF1	ENST00000495952.5	n.594G>A		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		5.8
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.013	D;D
Polyphen		0.13	B;.
Vest4		0.46
MutPred		0.39		Gain of catalytic residue at D202 (P = 0.117);.;
MVP		0.88
MPC		0.028
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.57
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs72619327; hg19: chr9-136219448;