chr2-27444510-GCTGTGGGAGGT-G

Position:

• chr2-27444510-GCTGTGGGAGGT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_015662.3(IFT172):​c.5161_5171del​(p.Thr1721ProfsTer40) variant causes a frameshift, 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT172 NM_015662.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.35

Genes affected

IFT172 (HGNC:30391): (intraflagellar transport 172) This gene encodes a subunit of the intraflagellar transport subcomplex IFT-B. Subcomplexes IFT-A and IFT-B are necessary for ciliary assembly and maintenance. Mutations in this gene have been associated with skeletal ciliopathies, with or without polydactyly, such as such short-rib thoracic dysplasias 1, 9 or 10. [provided by RefSeq, Mar 2014]

KRTCAP3 (HGNC:28943): (keratinocyte associated protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.017 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-27444510-GCTGTGGGAGGT-G is Pathogenic according to our data. Variant chr2-27444510-GCTGTGGGAGGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2949884.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT172	NM_015662.3	c.5161_5171del	p.Thr1721ProfsTer40	frameshift_variant, splice_region_variant	48/48	ENST00000260570.8	NP_056477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT172	ENST00000260570.8	c.5161_5171del	p.Thr1721ProfsTer40	frameshift_variant, splice_region_variant	48/48	1	NM_015662.3	ENSP00000260570	P1

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

This sequence change results in a frameshift in the IFT172 gene (p.Thr1721Profs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the IFT172 protein and extend the protein by 10 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IFT172-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the IFT172 protein in which other variant(s) (p.Cys1727Arg) have been determined to be pathogenic (PMID: 24140113). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-27667377;