2-27454631-C-A

Position:

chr2-27454631-C-A

Variant summary

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

The NM_015662.3(IFT172):c.3401G>T(p.Arg1134Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,613,892 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1134Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 27 hom. )

Consequence

IFT172
NM_015662.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.34

Variant links:

Genes affected

IFT172 (HGNC:30391): (intraflagellar transport 172) This gene encodes a subunit of the intraflagellar transport subcomplex IFT-B. Subcomplexes IFT-A and IFT-B are necessary for ciliary assembly and maintenance. Mutations in this gene have been associated with skeletal ciliopathies, with or without polydactyly, such as such short-rib thoracic dysplasias 1, 9 or 10. [provided by RefSeq, Mar 2014]

IFT172 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=0.0136809945).

BP6

Variant 2-27454631-C-A is Benign according to our data. Variant chr2-27454631-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 252701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27454631-C-A is described in Lovd as [Benign]. Variant chr2-27454631-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0051 (775/152062) while in subpopulation AMR AF= 0.00739 (113/15286). AF 95% confidence interval is 0.00629. There are 5 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT172	NM_015662.3 linkuse as main transcript	c.3401G>T	p.Arg1134Leu	missense_variant	31/48	ENST00000260570.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT172	ENST00000260570.8 linkuse as main transcript	c.3401G>T	p.Arg1134Leu	missense_variant	31/48	1	NM_015662.3	P1	Q9UG01-1

Frequencies

GnomAD3 genomes

AF:

0.00510

AC:

775

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.00767

GnomAD3 exomes

AF:

0.00536

AC:

1347

AN:

251406

Hom.:

AF XY:

0.00545

AC XY:

740

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00350

Gnomad ASJ exome

AF:

0.00685

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.0191

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00668

GnomAD4 exome

AF:

0.00550

AC:

8035

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

4040

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00360

Gnomad4 ASJ exome

AF:

0.00585

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00563

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.00510

AC:

775

AN:

152062

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

424

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.00527

Hom.:

Bravo

AF:

0.00397

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00488

AC:

593

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00589

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 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. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	IFT172: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.49

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.94

MVP

0.50

MPC

0.71

ClinPred

0.032

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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