rs143037947

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017503.5(SURF2):c.73C>T(p.Arg25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,516,852 control chromosomes in the GnomAD database, including 611 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 99 hom., cov: 32)

Exomes 𝑓: 0.021 ( 512 hom. )

Consequence

SURF2
NM_017503.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.20

Publications

4 publications found

Variant links:

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]

SURF2 links:

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

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015997291).

BP6

Variant 9-133356665-C-T is Benign according to our data. Variant chr9-133356665-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF2	NM_017503.5	MANE Select	c.73C>T	p.Arg25Cys	missense	Exon 1 of 6	NP_059973.4
SURF2	NM_001278928.2		c.73C>T	p.Arg25Cys	missense	Exon 1 of 6	NP_001265857.1
SURF1	NM_003172.4	MANE Select	c.-212G>A		upstream_gene	N/A	NP_003163.1	Q15526-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF2	ENST00000371964.5	TSL:1 MANE Select	c.73C>T	p.Arg25Cys	missense	Exon 1 of 6	ENSP00000361032.4	Q15527
SURF2	ENST00000934438.1		c.73C>T	p.Arg25Cys	missense	Exon 1 of 7	ENSP00000604497.1
SURF2	ENST00000875735.1		c.73C>T	p.Arg25Cys	missense	Exon 1 of 6	ENSP00000545794.1

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3105

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00491

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0826

Gnomad ASJ

AF:

0.0329

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0433

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0279

GnomAD2 exomes

AF:

0.0440

AC:

4894

AN:

111340

AF XY:

0.0396

show subpopulations

Gnomad AFR exome

AF:

0.00569

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.0380

Gnomad EAS exome

AF:

0.000501

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0333

GnomAD4 exome

AF:

0.0206

AC:

28147

AN:

1364806

Hom.:

512

Cov.:

AF XY:

0.0211

AC XY:

14229

AN XY:

673136

show subpopulations

African (AFR)

AF:

0.00353

AC:

104

AN:

29440

American (AMR)

AF:

0.108

AC:

3646

AN:

33792

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

878

AN:

24182

East Asian (EAS)

AF:

0.000296

AC:

AN:

33824

South Asian (SAS)

AF:

0.0473

AC:

3660

AN:

77382

European-Finnish (FIN)

AF:

0.0114

AC:

380

AN:

33442

Middle Eastern (MID)

AF:

0.0212

AC:

AN:

4630

European-Non Finnish (NFE)

AF:

0.0170

AC:

18164

AN:

1071146

Other (OTH)

AF:

0.0212

AC:

1207

AN:

56968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1391

2782

4173

5564

6955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

774

1548

2322

3096

3870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0205

AC:

3114

AN:

152046

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1651

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00492

AC:

204

AN:

41488

American (AMR)

AF:

0.0831

AC:

1271

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0329

AC:

114

AN:

3468

East Asian (EAS)

AF:

0.000388

AC:

AN:

5152

South Asian (SAS)

AF:

0.0433

AC:

209

AN:

4824

European-Finnish (FIN)

AF:

0.0129

AC:

136

AN:

10578

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0160

AC:

1090

AN:

67934

Other (OTH)

AF:

0.0276

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

142

284

426

568

710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0184

Hom.:

Bravo

AF:

0.0261

ESP6500AA

AF:

0.00286

AC:

ESP6500EA

AF:

0.0120

AC:

ExAC

AF:

0.0164

AC:

1473

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.9

(source)

DANN

Benign

0.93

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0060

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

PhyloP100

-3.2

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.9

REVEL

Benign

0.017

Sift

Benign

0.090

Sift4G

Benign

0.083

Vest4

0.049

MPC

0.079

ClinPred

0.0051

GERP RS

-5.3

PromoterAI

-0.065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over