chr20-43596472-G-A

Position:

chr20-43596472-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001323578.2(IFT52):c.-515G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000765 in 1,607,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

IFT52
NM_001323578.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.88

Variant links:

Genes affected

IFT52 (HGNC:15901): (intraflagellar transport 52) This gene encodes a conserved proline-rich protein that is a component of the intraflagellar transport-B (IFT-B) core complex. The encoded protein is essential for the integrity of the IFT-B core complex, and for biosynthesis and maintenance of cilia. Mutations in this gene are associated with ciliopathy that affects the skeleton. [provided by RefSeq, Oct 2016]

IFT52 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04679787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT52	NM_016004.5 link	c.157G>A	p.Val53Met	missense_variant	3/14	ENST00000373030.8	NP_057088.2	Q9Y366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IFT52	ENST00000373030.8 link	c.157G>A	p.Val53Met	missense_variant	3/14	1	NM_016004.5	ENSP00000362121.3	Q9Y366
IFT52	ENST00000373039.4 link	c.157G>A	p.Val53Met	missense_variant	3/14	5		ENSP00000362130.4	Q9Y366
IFT52	ENST00000486243.1 link	n.134G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

248554

Hom.:

AF XY:

0.0000670

AC XY:

AN XY:

134364

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1455256

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

724118

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000414

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000728

Hom.:

Bravo

AF:

0.000438

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 16 with or without polydactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 06, 2021

ACMG classification criteria: PM2 moderate, BP4 supporting -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 53 of the IFT52 protein (p.Val53Met). This variant is present in population databases (rs137979762, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with IFT52-related conditions. ClinVar contains an entry for this variant (Variation ID: 1427662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IFT52 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.047

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.94

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.075

T;T

Sift4G

Uncertain

0.059

T;T

Polyphen

1.0

D;D

Vest4

0.54

MVP

0.72

MPC

0.64

ClinPred

0.14

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.77

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