NM_017503.5:c.14C>A

Variant names:

• chr9-133356606-C-A
• rs1443228220
• NM_017503.5:c.14C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017503.5(SURF2):​c.14C>A​(p.Pro5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,372,696 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. P5L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SURF2 NM_017503.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.437
• Publications: 1 publications found

Genes affected

SURF2 (HGNC:11475): (surfeit 2) This gene shares a bidirectional promoter with surfeit 1 (SURF1; GeneID: 6834), which is located on the opposite strand. It encodes a conserved protein that is expressed in a variety of tissues. [provided by RefSeq, Jul 2013]

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, STRONG Submitted by: PanelApp Australia, G2P
• mitochondrial disease

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017503.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF2	NM_017503.5	MANE Select	c.14C>A	p.Pro5Gln	missense	Exon 1 of 6	NP_059973.4
	SURF2	NM_001278928.2		c.14C>A	p.Pro5Gln	missense	Exon 1 of 6	NP_001265857.1
	SURF1	NM_003172.4	MANE Select	c.-153G>T		upstream_gene	N/A	NP_003163.1	Q15526-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF2	ENST00000371964.5	TSL:1 MANE Select	c.14C>A	p.Pro5Gln	missense	Exon 1 of 6	ENSP00000361032.4	Q15527
	SURF2	ENST00000934438.1		c.14C>A	p.Pro5Gln	missense	Exon 1 of 7	ENSP00000604497.1
	SURF2	ENST00000875735.1		c.14C>A	p.Pro5Gln	missense	Exon 1 of 6	ENSP00000545794.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1372696 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 677420

African (AFR) AF: 0.00 AC: 0 AN: 29632

American (AMR) AF: 0.00 AC: 0 AN: 35052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24610

East Asian (EAS) AF: 0.0000293 AC: 1 AN: 34158

South Asian (SAS) AF: 0.00 AC: 0 AN: 78402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075218

Other (OTH) AF: 0.00 AC: 0 AN: 57364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.035	N
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.92	T
PhyloP100		0.44
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.098
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0040	D
Vest4		0.17
MutPred		0.83		Loss of phosphorylation at S2 (P = 0.1374)
MVP		0.45
MPC		0.34
ClinPred		0.99	D
GERP RS		0.91
PromoterAI		0.41	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1443228220; hg19: chr9-136223482;