Genetic Variant NM_003172.4:c.32_38dupTGCGGGC (chr9-133356415-C-CGCCCGCA) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003172.4(SURF1):c.32_38dupTGCGGGC(p.Leu16GlyfsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,379,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

SURF1
NM_003172.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.397

Publications

0 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 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 135 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-133356415-C-CGCCCGCA is Pathogenic according to our data. Variant chr9-133356415-C-CGCCCGCA is described in ClinVar as Pathogenic. ClinVar VariationId is 456665.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF1	NM_003172.4	MANE Select	c.32_38dupTGCGGGC	p.Leu16GlyfsTer46	frameshift	Exon 1 of 9	NP_003163.1	Q15526-1
SURF1	NM_001280787.1		c.-244_-238dupTGCGGGC		5_prime_UTR	Exon 1 of 8	NP_001267716.1	A0A087WYS9
SURF2	NM_017503.5	MANE Select	c.-178_-177insGCCCGCA		upstream_gene	N/A	NP_059973.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF1	ENST00000371974.8	TSL:1 MANE Select	c.32_38dupTGCGGGC	p.Leu16GlyfsTer46	frameshift	Exon 1 of 9	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4	TSL:1	c.-244_-238dupTGCGGGC		5_prime_UTR	Exon 1 of 8	ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000886676.1		c.32_38dupTGCGGGC	p.Leu16GlyfsTer46	frameshift	Exon 1 of 9	ENSP00000556735.1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000501

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.14e-7

AC:

AN:

1228866

Hom.:

Cov.:

AF XY:

0.00000166

AC XY:

AN XY:

602008

show subpopulations

African (AFR)

AF:

0.0000444

AC:

AN:

22546

American (AMR)

AF:

0.00

AC:

AN:

17026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19676

East Asian (EAS)

AF:

0.00

AC:

AN:

26748

South Asian (SAS)

AF:

0.00

AC:

AN:

56966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3504

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1002314

Other (OTH)

AF:

0.00

AC:

AN:

50050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000133

AC:

AN:

150142

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73350

show subpopulations

African (AFR)

AF:

0.0000501

AC:

AN:

39920

American (AMR)

AF:

0.00

AC:

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000189

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.40

Mutation Taster

=17/183

disease causing (ClinVar)

(source)

Splicing

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