9-133356757-CAGGGGAGAGGGGAG-CAGGGGAGAGGGGAGAGGGGAGAGGGGAG

Variant names:

• chr9-133356757-C-CAGGGGAGAGGGGAG
• rs587680893
• NM_017503.5:c.78+97_78+110dupGGGAGAGGGGAGAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017503.5(SURF2):​c.78+97_78+110dupGGGAGAGGGGAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,199,314 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: SURF2 NM_017503.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 0 publications found

Genes affected

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]

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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017503.5. 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
	SURF2	NM_017503.5	MANE Select	c.78+97_78+110dupGGGAGAGGGGAGAG		intron	N/A	NP_059973.4
	SURF2	NM_001278928.2		c.78+97_78+110dupGGGAGAGGGGAGAG		intron	N/A	NP_001265857.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF2	ENST00000371964.5	TSL:1 MANE Select	c.78+97_78+110dupGGGAGAGGGGAGAG		intron	N/A	ENSP00000361032.4	Q15527
	SURF2	ENST00000934438.1		c.78+97_78+110dupGGGAGAGGGGAGAG		intron	N/A	ENSP00000604497.1
	SURF2	ENST00000875735.1		c.78+97_78+110dupGGGAGAGGGGAGAG		intron	N/A	ENSP00000545794.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000250 AC: 3 AN: 1199314 Hom.: 0 Cov.: 14 AF XY: 0.00000171 AC XY: 1 AN XY: 584808

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25666

American (AMR) AF: 0.00 AC: 0 AN: 23194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18852

East Asian (EAS) AF: 0.00 AC: 0 AN: 31498

South Asian (SAS) AF: 0.00 AC: 0 AN: 62790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3492

European-Non Finnish (NFE) AF: 0.00000315 AC: 3 AN: 953334

Other (OTH) AF: 0.00 AC: 0 AN: 50416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0186682), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061

Splicing

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

Other links and lift over

dbSNP: rs587680893; hg19: chr9-136223633;