rs786205142

chr14-60509929-AAACCG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_007374.3(SIX6):c.532_536del(p.Asn178ProfsTer142) variant causes a frameshift 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX6 NM_007374.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

Genes affected

SIX6 (HGNC:10892): (SIX homeobox 6) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.282 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-60509929-AAACCG-A is Pathogenic according to our data. Variant chr14-60509929-AAACCG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-60509929-AAACCG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX6	NM_007374.3	c.532_536del	p.Asn178ProfsTer142	frameshift_variant	1/2	ENST00000327720.6
C14orf39	XM_047431324.1	c.-144+5461_-144+5465del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX6	ENST00000327720.6	c.532_536del	p.Asn178ProfsTer142	frameshift_variant	1/2	1	NM_007374.3	P1
C14orf39	ENST00000556799.1	c.-144+5461_-144+5465del		intron_variant		4

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2017	The c.532_536delAACCG variant in the SIX6 gene has been reported previously in the homozygous state in two siblings with micropthalmia (Aldahmesh et al., 2013). The c.532_536delAACCG variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 142 of the new reading frame, with the last 69 amnio acids being replaced by 141 aberrant amino acids, denoted p.Asn178ProfsX142. This alteration may interfere with the proper formation and/or function of the SIX6 protein. The c.532_536delAACCG variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server) The c.532_536delAACCG variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205142; hg19: chr14-60976647;