dbSNP rs782190413: SURF1:p.Arg192Trp (chr9-133352708-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003172.4(SURF1):c.574C>T(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.659

Publications

9 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, 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: Pathogenic. The variant received 19 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-133352707-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1329011.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, 0.965

PP5

Variant 9-133352708-G-A is Pathogenic according to our data. Variant chr9-133352708-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 215235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	NM_003172.4	MANE Select	c.574C>T	p.Arg192Trp	missense	Exon 6 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.247C>T	p.Arg83Trp	missense	Exon 5 of 8	NP_001267716.1	A0A087WYS9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF1	ENST00000371974.8	TSL:1 MANE Select	c.574C>T	p.Arg192Trp	missense	Exon 6 of 9	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4	TSL:1	c.247C>T	p.Arg83Trp	missense	Exon 5 of 8	ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000886676.1		c.544C>T	p.Arg182Trp	missense	Exon 6 of 9	ENSP00000556735.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249494

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461090

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111792

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leigh syndrome (2)

not provided (2)

Charcot-Marie-Tooth disease type 4K (1)

Charcot-Marie-Tooth disease type 4K;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 (1)

Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.6

PhyloP100

0.66

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.71

MVP

0.95

MPC

0.20

ClinPred

0.95

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.89

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.080

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