3-129483546-G-T

Variant names:

• chr3-129483546-G-T
• rs786205566
• NM_052989.3:c.1715G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP3_Moderate PP5_Moderate

The NM_052989.3(IFT122):​c.1715G>T​(p.Gly572Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.43

Genes affected

IFT122 (HGNC:13556): (intraflagellar transport 122) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_052989.3 (IFT122) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 3-129483546-G-T is Pathogenic according to our data. Variant chr3-129483546-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191184.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129483546-G-T is described in Lovd as [Pathogenic]. Variant chr3-129483546-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT122	NM_052989.3	c.1715G>T	p.Gly572Val	missense_variant	Exon 15 of 30	ENST00000348417.7	NP_443715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT122	ENST00000348417.7	c.1715G>T	p.Gly572Val	missense_variant	Exon 15 of 30	1	NM_052989.3	ENSP00000324005.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cranioectodermal dysplasia 1 Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;.;.;.;.;.;.;D;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;.;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		0.96, 0.99	.;.;D;.;.;.;.;D;.
Vest4		0.92
MutPred		0.56		.;.;.;.;.;.;.;Loss of sheet (P = 0.0457);.;
MVP		0.74
MPC		0.63
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.73
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205566; hg19: chr3-129202389;