4-127669126-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_015693.4(INTU):​c.1063G>T​(p.Glu355*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

INTU
NM_015693.4 stop_gained

Scores

4
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.03
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 4-127669126-G-T is Pathogenic according to our data. Variant chr4-127669126-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504481.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INTUNM_015693.4 linkc.1063G>T p.Glu355* stop_gained Exon 5 of 16 ENST00000335251.11 NP_056508.2 Q9ULD6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INTUENST00000335251.11 linkc.1063G>T p.Glu355* stop_gained Exon 5 of 16 1 NM_015693.4 ENSP00000334003.5 Q9ULD6-1
INTUENST00000503952.5 linkn.1063G>T non_coding_transcript_exon_variant Exon 5 of 17 1 ENSP00000421995.1 Q9ULD6-3
INTUENST00000503626.5 linkn.1063G>T non_coding_transcript_exon_variant Exon 5 of 18 2 ENSP00000426287.1 Q9ULD6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
23
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 20 with polydactyly Pathogenic:2
Oct 15, 2018
SIB Swiss Institute of Bioinformatics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Short-rib thoracic dysplasia 20 with polydactyly, autosomal recessive. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/27158779). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PVS1-Moderate => PVS1 downgraded in strength to Moderate. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Jul 16, 2019
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Short rib-polydactyly syndrome Pathogenic:1
May 09, 2016
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.96
D
Vest4
0.41
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.44
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.44
Position offset: 28

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.

Other links and lift over

dbSNP: rs1037828930; hg19: chr4-128590281; COSMIC: COSV56538662; API