3-129492134-G-C

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.1993-7G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,604,430 control chromosomes in the GnomAD database, including 63,735 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (17995 hom., cov: 32)
  • Exomes 𝑓: 0.20 (45740 hom.)
• Consequence: IFT122 NM_052989.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002742
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.306

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 3-129492134-G-C is Benign according to our data. Variant chr3-129492134-G-C is described in ClinVar as [Benign]. Clinvar id is 194901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129492134-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3	c.1993-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7	c.1993-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_052989.3

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58054 AN: 151928 Hom.: 17931 Cov.: 32

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.348

GnomAD3 exomes AF: 0.282 AC: 70818 AN: 251436 Hom.: 15752 AF XY: 0.272 AC XY: 36985 AN XY: 135892

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.676

Gnomad SAS exome AF: 0.373

Gnomad FIN exome AF: 0.0704

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.203 AC: 295254 AN: 1452384 Hom.: 45740 Cov.: 30 AF XY: 0.207 AC XY: 149729 AN XY: 723160

Gnomad4 AFR exome AF: 0.854

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.0743

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.383 AC: 58183 AN: 152046 Hom.: 17995 Cov.: 32 AF XY: 0.383 AC XY: 28431 AN XY: 74290

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.0745

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.349

Alfa AF: 0.161 Hom.: 827

Bravo AF: 0.420

EpiCase AF: 0.173

EpiControl AF: 0.179

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Cranioectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.7
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.010
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: rs2285354; hg19: chr3-129210977; COSMIC: COSV56200944; COSMIC: COSV56200944;