rs863224228

Variant names:

• chr9-133354661-GGCTGGCAGA-AT
• rs863224228
• NM_003172.4:c.312_321delTCTGCCAGCCinsAT

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PVS1 PS3 PM2 PP2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.312_321delTCTGCCAGCCinsAT​(p.Leu105fs) variant causes a frameshift, missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002520043: PS3, PM2, PS4_supporting **Correction based on instructions**: Since the input directly mentions PS3 but does not provide a specific description of functional studies, the correct response according to the instructions is: `no`" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P104P) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SURF1 NM_003172.4 frameshift, missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.54
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002520043: PS3, PM2, PS4_supporting **Correction based on instructions**: Since the input directly mentions PS3 but does not provide a specific description of functional studies, the correct response according to the instructions is: `no`; SCV004032897: PS3:Supporting; SCV000698177: Biochemical enzymatic analysis in patient cells carrying this variant are show impaired enzymatic activity (Tiranti_1998, Lim_2014).
• PM2: Very rare variant in population databases, with high coverage
• 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 mitochondrial complex IV deficiency, nuclear type 1, Leigh syndrome, mitochondrial disease, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with leukodystrophy, Leigh syndrome with cardiomyopathy.
• PP5: Variant 9-133354661-GGCTGGCAGA-AT is Pathogenic according to our data. Variant chr9-133354661-GGCTGGCAGA-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 215237.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.312_321delTCTGCCAGCCinsAT	p.Leu105fs	frameshift missense splice_region	Exon 4 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.-16_-7delTCTGCCAGCCinsAT		splice_region	Exon 3 of 8	NP_001267716.1	A0A087WYS9
	SURF1	NM_001280787.1		c.-16_-7delTCTGCCAGCCinsAT		5_prime_UTR	Exon 3 of 8	NP_001267716.1	A0A087WYS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	ENST00000371974.8	TSL:1 MANE Select	c.312_321delTCTGCCAGCCinsAT	p.Leu105fs	frameshift missense splice_region	Exon 4 of 9	ENSP00000361042.3	Q15526-1
	SURF1	ENST00000615505.4	TSL:1	c.-16_-7delTCTGCCAGCCinsAT		splice_region	Exon 3 of 8	ENSP00000482067.1	A0A087WYS9
	SURF1	ENST00000615505.4	TSL:1	c.-16_-7delTCTGCCAGCCinsAT		5_prime_UTR	Exon 3 of 8	ENSP00000482067.1	A0A087WYS9

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Leigh syndrome (4)
1	-	-	Charcot-Marie-Tooth disease type 4K;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	SURF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs863224228; hg19: chr9-136221516; COSMIC: COSV107326882; COSMIC: COSV107326882;