3-129483473-C-T

Position:

• chr3-129483473-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052989.3(IFT122):​c.1654-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,612,952 control chromosomes in the GnomAD database, including 11,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1589 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10259 hom.)
• Consequence: IFT122 NM_052989.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003809
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.204

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-129483473-C-T is Benign according to our data. Variant chr3-129483473-C-T is described in ClinVar as [Benign]. Clinvar id is 262268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129483473-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3	c.1654-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7	c.1654-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_052989.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19510 AN: 151760 Hom.: 1584 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.116 AC: 28937 AN: 250330 Hom.: 2297 AF XY: 0.123 AC XY: 16616 AN XY: 135454

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.0699

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0769

Gnomad SAS exome AF: 0.251

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0956

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.108 AC: 157618 AN: 1461074 Hom.: 10259 Cov.: 32 AF XY: 0.112 AC XY: 81773 AN XY: 726888

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0730

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.0645

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.0410

Gnomad4 NFE exome AF: 0.0975

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.129 AC: 19535 AN: 151878 Hom.: 1589 Cov.: 32 AF XY: 0.128 AC XY: 9515 AN XY: 74230

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0807

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.0396

Gnomad4 NFE AF: 0.0942

Gnomad4 OTH AF: 0.139

Alfa AF: 0.0751 Hom.: 144

Bravo AF: 0.135

Asia WGS AF: 0.205 AC: 715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cranioectodermal dysplasia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cranioectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs112066509; hg19: chr3-129202316; COSMIC: COSV56208786; COSMIC: COSV56208786;