4-127633092-C-G

Position:

chr4-127633092-C-G

Variant summary

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

The NM_015693.4(INTU):c.58C>G(p.Pro20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

INTU
NM_015693.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.210

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 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=0.04861009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTU	NM_015693.4 link	c.58C>G	p.Pro20Ala	missense_variant	1/16	ENST00000335251.11	NP_056508.2	Q9ULD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INTU	ENST00000335251.11 link	c.58C>G	p.Pro20Ala	missense_variant	1/16	1	NM_015693.4	ENSP00000334003.5	Q9ULD6-1
INTU	ENST00000503952.5 link	n.58C>G		non_coding_transcript_exon_variant	1/17	1		ENSP00000421995.1	Q9ULD6-3
INTU	ENST00000504491.1 link	c.89+9601C>G		intron_variant		4		ENSP00000422550.1	J3QTA5
INTU	ENST00000503626.5 link	n.58C>G		non_coding_transcript_exon_variant	1/18	2		ENSP00000426287.1	Q9ULD6-2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251364

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

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:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461624

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.58C>G (p.P20A) alteration is located in exon 1 (coding exon 1) of the INTU gene. This alteration results from a C to G substitution at nucleotide position 58, causing the proline (P) at amino acid position 20 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2024

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 20 of the INTU protein (p.Pro20Ala). This variant is present in population databases (rs747779931, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with INTU-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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

0.065

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

DANN

Benign

0.73

DEOGEN2

Benign

0.13

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.56

M_CAP

Benign

0.0021

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

0.44

REVEL

Benign

0.081

Sift

Benign

0.11

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.19

MPC

0.11

ClinPred

0.025

GERP RS

1.3

Varity_R

0.033

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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