Genetic Variant SURF1:p.Ala56Gly (chr9-133354897-G-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003172.4(SURF1):c.167C>G(p.Ala56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,944 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A56A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 35 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.737

Publications

13 publications found

Variant links:

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

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028353333).

BP6

Variant 9-133354897-G-C is Benign according to our data. Variant chr9-133354897-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1871/152268) while in subpopulation AFR AF = 0.0354 (1468/41526). AF 95% confidence interval is 0.0338. There are 28 homozygotes in GnomAd4. There are 892 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003172.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	NM_003172.4	MANE Select	c.167C>G	p.Ala56Gly	missense	Exon 3 of 9	NP_003163.1
	SURF1	NM_001280787.1		c.-161C>G		5_prime_UTR	Exon 2 of 8	NP_001267716.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SURF1	ENST00000371974.8	TSL:1 MANE Select	c.167C>G	p.Ala56Gly	missense	Exon 3 of 9	ENSP00000361042.3
SURF1	ENST00000615505.4	TSL:1	c.-161C>G		5_prime_UTR	Exon 2 of 8	ENSP00000482067.1
SURF1	ENST00000437995.1	TSL:5	n.113C>G		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1866

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00837

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.00510

AC:

1283

AN:

251400

AF XY:

0.00458

show subpopulations

Gnomad AFR exome

AF:

0.0358

Gnomad AMR exome

AF:

0.00564

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00348

AC:

5088

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

2481

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.0339

AC:

1136

AN:

33480

American (AMR)

AF:

0.00631

AC:

282

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00368

AC:

317

AN:

86258

European-Finnish (FIN)

AF:

0.000564

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.0210

AC:

121

AN:

5760

European-Non Finnish (NFE)

AF:

0.00251

AC:

2791

AN:

1112000

Other (OTH)

AF:

0.00639

AC:

386

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

372

744

1117

1489

1861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0123

AC:

1871

AN:

152268

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0354

AC:

1468

AN:

41526

American (AMR)

AF:

0.00836

AC:

128

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

68018

Other (OTH)

AF:

0.0142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000653

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0320

AC:

141

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00544

AC:

661

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22488715, 27884173, 16091512)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SURF1: BP4, BS1, BS2

not specified

Benign:1

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leigh syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.90

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.29

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.35

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.8

PhyloP100

0.74

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.70

REVEL

Benign

0.12

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.32

Vest4

0.20

MVP

0.68

MPC

0.031

ClinPred

0.0030

GERP RS

2.1

Varity_R

0.032

gMVP

0.46

Mutation Taster

=94/6

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over