Variant 4-127663438-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_015693.4(INTU):c.826C>T(p.Gln276*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

INTU
NM_015693.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.350

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 Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-127663438-C-T is Pathogenic according to our data. Variant chr4-127663438-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504483.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTU	NM_015693.4 linkuse as main transcript	c.826C>T	p.Gln276*	stop_gained	4/16	ENST00000335251.11	NP_056508.2	Q9ULD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INTU	ENST00000335251.11 linkuse as main transcript	c.826C>T	p.Gln276*	stop_gained	4/16	1	NM_015693.4	ENSP00000334003.5	Q9ULD6-1
INTU	ENST00000503952.5 linkuse as main transcript	n.826C>T		non_coding_transcript_exon_variant	4/17	1		ENSP00000421995.1	Q9ULD6-3
INTU	ENST00000503626.5 linkuse as main transcript	n.826C>T		non_coding_transcript_exon_variant	4/18	2		ENSP00000426287.1	Q9ULD6-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461028

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000205

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 7/20 with polydactyly, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 02, 2018

- -

Short-rib thoracic dysplasia 20 with polydactyly

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Oct 15, 2018

This variant is interpreted as Likely Pathogenic, for Short-rib thoracic dysplasia 7/20 with polydactyly, digenic. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/27158779). PVS1-Moderate => PVS1 downgraded in strength to Moderate. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change creates a premature translational stop signal (p.Gln276*) in the INTU gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in INTU cause disease. This variant is present in population databases (rs373900644, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 27158779). ClinVar contains an entry for this variant (Variation ID: 504483). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

0.074

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.035

Vest4

0.20

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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