chr3-129467081-G-A

Variant names:

• chr3-129467081-G-A
• rs56379561
• NM_052989.3:c.740+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052989.3(IFT122):​c.740+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,610,426 control chromosomes in the GnomAD database, including 12,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1709 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10357 hom.)
• Consequence: IFT122 NM_052989.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.274
• Publications: 5 publications found

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]

IFT122 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-129467081-G-A is Benign according to our data. Variant chr3-129467081-G-A is described in ClinVar as Benign. ClinVar VariationId is 262273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052989.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT122	NM_052989.3	MANE Select	c.740+15G>A		intron	N/A	NP_443715.1
	IFT122	NM_052985.4		c.893+15G>A		intron	N/A	NP_443711.2
	IFT122	NM_001410808.1		c.740+15G>A		intron	N/A	NP_001397737.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT122	ENST00000348417.7	TSL:1 MANE Select	c.740+15G>A		intron	N/A	ENSP00000324005.4
	IFT122	ENST00000296266.7	TSL:1	c.893+15G>A		intron	N/A	ENSP00000296266.3
	IFT122	ENST00000507564.5	TSL:1	c.717-2261G>A		intron	N/A	ENSP00000425536.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20157 AN: 152144 Hom.: 1703 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.117 AC: 29110 AN: 249336 AF XY: 0.124

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.0708

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0769

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.108 AC: 157776 AN: 1458164 Hom.: 10357 Cov.: 32 AF XY: 0.113 AC XY: 81840 AN XY: 725496

African (AFR) AF: 0.230 AC: 7691 AN: 33388

American (AMR) AF: 0.0739 AC: 3301 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4376 AN: 26116

East Asian (EAS) AF: 0.0644 AC: 2555 AN: 39680

South Asian (SAS) AF: 0.248 AC: 21391 AN: 86140

European-Finnish (FIN) AF: 0.0409 AC: 2166 AN: 52910

Middle Eastern (MID) AF: 0.164 AC: 827 AN: 5040

European-Non Finnish (NFE) AF: 0.0974 AC: 108133 AN: 1109998

Other (OTH) AF: 0.122 AC: 7336 AN: 60216

GnomAD4 genome AF: 0.133 AC: 20183 AN: 152262 Hom.: 1709 Cov.: 33 AF XY: 0.132 AC XY: 9835 AN XY: 74462

African (AFR) AF: 0.220 AC: 9145 AN: 41510

American (AMR) AF: 0.106 AC: 1627 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3468

East Asian (EAS) AF: 0.0811 AC: 421 AN: 5188

South Asian (SAS) AF: 0.240 AC: 1159 AN: 4824

European-Finnish (FIN) AF: 0.0390 AC: 414 AN: 10620

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0942 AC: 6410 AN: 68028

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.123 Hom.: 300

Bravo AF: 0.139

Asia WGS AF: 0.204 AC: 714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 13, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cranioectodermal dysplasia 1 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cranioectodermal dysplasia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.61
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs56379561; hg19: chr3-129185924; COSMIC: COSV56203848; COSMIC: COSV56203848;