NM_052989.3:c.2375+33G>T

Variant names:

• chr3-129500101-G-T
• rs6799876
• NM_052989.3:c.2375+33G>T

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.2375+33G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,612,318 control chromosomes in the GnomAD database, including 11,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1596 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10250 hom.)
• Consequence: IFT122 NM_052989.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.756
• Publications: 8 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=-0.78).
• BP6: Variant 3-129500101-G-T is Benign according to our data. Variant chr3-129500101-G-T is described in ClinVar as Benign. ClinVar VariationId is 262271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT122	NM_052989.3	c.2375+33G>T		intron_variant	Intron 19 of 29	ENST00000348417.7	NP_443715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT122	ENST00000348417.7	c.2375+33G>T		intron_variant	Intron 19 of 29	1	NM_052989.3	ENSP00000324005.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19544 AN: 152054 Hom.: 1591 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: 0.0818

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.115 AC: 29015 AN: 251220 AF XY: 0.123

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.0699

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0768

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0956

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.108 AC: 157543 AN: 1460146 Hom.: 10250 Cov.: 30 AF XY: 0.113 AC XY: 81764 AN XY: 726484

African (AFR) AF: 0.216 AC: 7227 AN: 33422

American (AMR) AF: 0.0730 AC: 3263 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4376 AN: 26120

East Asian (EAS) AF: 0.0645 AC: 2560 AN: 39686

South Asian (SAS) AF: 0.249 AC: 21417 AN: 86180

European-Finnish (FIN) AF: 0.0410 AC: 2189 AN: 53394

Middle Eastern (MID) AF: 0.160 AC: 921 AN: 5766

European-Non Finnish (NFE) AF: 0.0975 AC: 108298 AN: 1110526

Other (OTH) AF: 0.121 AC: 7292 AN: 60334

GnomAD4 genome AF: 0.129 AC: 19569 AN: 152172 Hom.: 1596 Cov.: 32 AF XY: 0.128 AC XY: 9538 AN XY: 74404

African (AFR) AF: 0.207 AC: 8588 AN: 41484

American (AMR) AF: 0.104 AC: 1588 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 578 AN: 3472

East Asian (EAS) AF: 0.0812 AC: 420 AN: 5172

South Asian (SAS) AF: 0.240 AC: 1153 AN: 4808

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0941 AC: 6402 AN: 68014

Other (OTH) AF: 0.139 AC: 295 AN: 2116

Alfa AF: 0.113 Hom.: 3068

Bravo AF: 0.135

Asia WGS AF: 0.205 AC: 716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.7
DANN	Benign	0.79
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6799876; hg19: chr3-129218944; COSMIC: COSV56208808; COSMIC: COSV56208808;