rs751222088

Variant names:

• chr12-110127467-G-C
• rs751222088
• NM_014055.4:c.87G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_014055.4(IFT81):​c.87G>C​(p.Leu29Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.16
• Publications: 1 publications found

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]

IFT81 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 19 with or without polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 12-110127467-G-C is Pathogenic according to our data. Variant chr12-110127467-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT81	NM_014055.4	c.87G>C	p.Leu29Phe	missense_variant	Exon 2 of 19	ENST00000242591.10	NP_054774.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT81	ENST00000242591.10	c.87G>C	p.Leu29Phe	missense_variant	Exon 2 of 19	1	NM_014055.4	ENSP00000242591.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000366 AC: 9 AN: 245732 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000808

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1458082 Hom.: 0 Cov.: 30 AF XY: 0.000163 AC XY: 118 AN XY: 725172

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000193 AC: 214 AN: 1110438

Other (OTH) AF: 0.0000332 AC: 2 AN: 60224

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000724 AC: 3 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short-rib thoracic dysplasia 19 with or without polydactyly Pathogenic:1

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Short-rib thoracic dysplasia 19 with or without polydactyly, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (https://www.ncbi.nlm.nih.gov/pubmed/27666822). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/27666822). -

not provided Pathogenic:1

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 29 of the IFT81 protein (p.Leu29Phe). This variant is present in population databases (rs751222088, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome and/or clinical features of short-rib thoracic dystrophy (PMID: 27666822; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495122). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IFT81 protein function with a positive predictive value of 80%. Studies have shown that this missense change alters IFT81 gene expression (PMID: 27666822). For these reasons, this variant has been classified as Pathogenic. -

SHORT-RIB THORACIC DYSPLASIA 19 WITHOUT POLYDACTYLY Pathogenic:1

Feb 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.5	M;M;M;.
PhyloP100		1.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.018	D;T;T;D
Polyphen		1.0	D;D;D;.
Vest4		0.76
MutPred		0.38		Gain of catalytic residue at D27 (P = 5e-04);Gain of catalytic residue at D27 (P = 5e-04);Gain of catalytic residue at D27 (P = 5e-04);Gain of catalytic residue at D27 (P = 5e-04);
MVP		0.91
MPC		0.61
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.32
gMVP		0.64
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs751222088; hg19: chr12-110565272;