rs61744639

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052989.3(IFT122):c.1273C>T(p.Arg425Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00473 in 1,614,106 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R425R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 41 hom. )

Consequence

IFT122
NM_052989.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.70

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009804696).

BP6

Variant 3-129478141-C-T is Benign according to our data. Variant chr3-129478141-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 288335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129478141-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (679/152272) while in subpopulation NFE AF= 0.00703 (478/68026). AF 95% confidence interval is 0.00651. There are 4 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3 linkuse as main transcript	c.1273C>T	p.Arg425Trp	missense_variant	12/30	ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7 linkuse as main transcript	c.1273C>T	p.Arg425Trp	missense_variant	12/30	1	NM_052989.3		Q9HBG6-1

Frequencies

GnomAD3 genomes

AF:

0.00447

AC:

680

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00517

AC:

1300

AN:

251436

Hom.:

AF XY:

0.00539

AC XY:

733

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.0333

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00470

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00586

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00476

AC:

6953

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

3646

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00392

Gnomad4 FIN exome

AF:

0.00389

Gnomad4 NFE exome

AF:

0.00468

Gnomad4 OTH exome

AF:

0.00485

GnomAD4 genome

AF:

0.00446

AC:

679

AN:

152272

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

315

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.0343

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.00703

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00687

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00475

AC:

577

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	IFT122: BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2017	- -

Cranioectodermal dysplasia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.0098

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.49

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;D;.;.;.;.;D

Vest4

0.52

MVP

0.95

MPC

0.78

ClinPred

0.024

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over