rs863224926

Positions:

• chr9-133356268-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.106+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SURF1 NM_003172.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133356268-C-G is Pathogenic according to our data. Variant chr9-133356268-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133356268-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4	c.106+1G>C		splice_donor_variant		ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.-222+132G>C		intron_variant			NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.106+1G>C		splice_donor_variant		1	NM_003172.4	ENSP00000361042	P1
SURF1	ENST00000615505.4	c.-222+132G>C		intron_variant		1		ENSP00000482067
SURF1	ENST00000463965.1	n.330G>C		non_coding_transcript_exon_variant	2/2	3
SURF1	ENST00000437995.1	n.52+1G>C		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2016	Variant summary: The SURF1 c.106+1G>C variant involves the alteration of a highly conserved canonical intronic nucleotide at the splice donor site in intron 2. 5/5 splice prediction tools predict that this variant abolishes the 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/11676 control chromosomes at a frequency of 0.0000856, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). In a published study, this variant has been reported in one LS patient in homozygous state (Lee_2012). In another unpublished report, the variant has been reported in one LS patient in homozygous state, parents being heterozygous carriers and functional study showed skipping of exon 2 (Akkouh I_Thesis_2015 (Department of Molecular Biosciences, Unversity of Oslo)). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic until other published results are reported. -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jun 12, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224926; hg19: chr9-136223123;