3-129460808-ATT-AT

Variant names:

• chr3-129460808-AT-A
• rs201674500
• NM_052989.3:c.273-417delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_052989.3(IFT122):​c.273-417delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,519,220 control chromosomes in the GnomAD database, including 1,173 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (330 hom., cov: 32)
  • Exomes 𝑓: 0.012 (843 hom.)
• Consequence: IFT122 NM_052989.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 3-129460808-AT-A is Benign according to our data. Variant chr3-129460808-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT122	NM_052989.3	c.273-417delT		intron_variant	Intron 4 of 29	ENST00000348417.7	NP_443715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT122	ENST00000348417.7	c.273-419delT		intron_variant	Intron 4 of 29	1	NM_052989.3	ENSP00000324005.4

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5771 AN: 152098 Hom.: 331 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0233 AC: 5856 AN: 251172 AF XY: 0.0253

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00549

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0154

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0119 AC: 16295 AN: 1367004 Hom.: 843 Cov.: 22 AF XY: 0.0143 AC XY: 9814 AN XY: 685800

African (AFR) AF: 0.120 AC: 3759 AN: 31316

American (AMR) AF: 0.00670 AC: 299 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25600

East Asian (EAS) AF: 0.0149 AC: 584 AN: 39196

South Asian (SAS) AF: 0.103 AC: 8697 AN: 84314

European-Finnish (FIN) AF: 0.000338 AC: 18 AN: 53266

Middle Eastern (MID) AF: 0.0100 AC: 56 AN: 5586

European-Non Finnish (NFE) AF: 0.00190 AC: 1951 AN: 1025828

Other (OTH) AF: 0.0162 AC: 928 AN: 57290

GnomAD4 genome AF: 0.0380 AC: 5777 AN: 152216 Hom.: 330 Cov.: 32 AF XY: 0.0381 AC XY: 2835 AN XY: 74438

African (AFR) AF: 0.115 AC: 4785 AN: 41490

American (AMR) AF: 0.0118 AC: 180 AN: 15294

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

East Asian (EAS) AF: 0.0182 AC: 94 AN: 5174

South Asian (SAS) AF: 0.106 AC: 514 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68032

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0177 Hom.: 23

Bravo AF: 0.0399

Asia WGS AF: 0.0790 AC: 275 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
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: rs201674500; hg19: chr3-129179651;