4-127687772-G-A

Position:

chr4-127687772-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015693.4(INTU):c.1354G>A(p.Ala452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,458 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 17 hom. )

Consequence

INTU
NM_015693.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 0.0190

Variant links:

Genes affected

INTU (HGNC:29239): (inturned planar cell polarity protein) Involved in embryonic digit morphogenesis; roof of mouth development; and tongue morphogenesis. Located in ciliary basal body and motile cilium. Implicated in asphyxiating thoracic dystrophy and orofaciodigital syndrome XVII. [provided by Alliance of Genome Resources, Apr 2022]

INTU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004006952).

BP6

Variant 4-127687772-G-A is Benign according to our data. Variant chr4-127687772-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504485.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00188 (286/152184) while in subpopulation SAS AF= 0.00767 (37/4822). AF 95% confidence interval is 0.00572. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTU	NM_015693.4 linkuse as main transcript	c.1354G>A	p.Ala452Thr	missense_variant	8/16	ENST00000335251.11	NP_056508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTU	ENST00000335251.11 linkuse as main transcript	c.1354G>A	p.Ala452Thr	missense_variant	8/16	1	NM_015693.4	ENSP00000334003	P1	Q9ULD6-1
INTU	ENST00000503952.5 linkuse as main transcript	c.*111G>A		3_prime_UTR_variant, NMD_transcript_variant	9/17	1		ENSP00000421995		Q9ULD6-3
INTU	ENST00000503626.5 linkuse as main transcript	c.*2621G>A		3_prime_UTR_variant, NMD_transcript_variant	10/18	2		ENSP00000426287		Q9ULD6-2
INTU	ENST00000506283.1 linkuse as main transcript			upstream_gene_variant		3		ENSP00000426171

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00420

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00263

AC:

660

AN:

250842

Hom.:

AF XY:

0.00301

AC XY:

408

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00912

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00245

AC:

3578

AN:

1461274

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1932

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00959

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152184

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00419

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00767

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00298

AC:

362

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Growth delay;C0687120:Nephronophthisis

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 09, 2016

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

INTU-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.1

DANN

Benign

0.88

DEOGEN2

Benign

0.21

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.56

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.35

REVEL

Benign

0.0070

Sift

Benign

0.22

Sift4G

Benign

0.58

Polyphen

0.14

Vest4

0.14

MVP

0.081

MPC

0.11

ClinPred

0.0012

GERP RS

1.3

Varity_R

0.024

gMVP

0.53

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