rs864309658

Positions:

• chr12-110218207-AGGACC-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The ENST00000242591.10(IFT81):​c.2015_2019del​(p.Asp672AlafsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,562,968 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E671E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: IFT81 ENST00000242591.10 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.40

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 848 codons.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000432 (61/1410686) while in subpopulation MID AF= 0.00164 (9/5500). AF 95% confidence interval is 0.000853. There are 1 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT81	NM_014055.4	c.2015_2019del	p.Asp672AlafsTer15	frameshift_variant	19/19	ENST00000242591.10	NP_054774.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT81	ENST00000242591.10	c.2015_2019del	p.Asp672AlafsTer15	frameshift_variant	19/19	1	NM_014055.4	ENSP00000242591	P1
IFT81	ENST00000552912.5	c.2015_2019del	p.Asp672AlafsTer15	frameshift_variant	19/19	1		ENSP00000449718	P1
IFT81	ENST00000550748.1	n.2479_2483del		non_coding_transcript_exon_variant	4/4	1
IFT81	ENST00000550156.5	c.*245_*249del		3_prime_UTR_variant, NMD_transcript_variant	20/20	2		ENSP00000446895

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000432 AC: 61 AN: 1410686 Hom.: 1 AF XY: 0.0000458 AC XY: 32 AN XY: 699238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000333

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000265

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2023	This sequence change results in a frameshift in the IFT81 gene (p.Asp672Alafs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the IFT81 protein and extend the protein by 9 additional amino acid residues. This variant is present in population databases (rs763354429, gnomAD 0.04%). This frameshift has been observed in individual(s) with retinal disease and intellectual disability (PMID: 26275418). ClinVar contains an entry for this variant (Variation ID: 218893). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on IFT81 function (PMID: 26275418). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Ciliopathy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2015

- -

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: rs864309658; hg19: chr12-110656012;