Genetic Variant NM_015693.4:c.1063G>C (chr4-127669126-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015693.4(INTU):c.1063G>C(p.Glu355Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,386,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

INTU
NM_015693.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.03

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

orofaciodigital syndrome 17
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
short-rib thoracic dysplasia 20 with polydactyly
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

INTU links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2707737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTU	NM_015693.4 link	c.1063G>C	p.Glu355Gln	missense_variant	Exon 5 of 16	ENST00000335251.11	NP_056508.2	Q9ULD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INTU	ENST00000335251.11 link	c.1063G>C	p.Glu355Gln	missense_variant	Exon 5 of 16	1	NM_015693.4	ENSP00000334003.5	Q9ULD6-1
INTU	ENST00000503952.5 link	n.1063G>C		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000421995.1	Q9ULD6-3
INTU	ENST00000503626.5 link	n.1063G>C		non_coding_transcript_exon_variant	Exon 5 of 18	2		ENSP00000426287.1	Q9ULD6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1386490

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31106

American (AMR)

AF:

0.00

AC:

AN:

39908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24668

East Asian (EAS)

AF:

0.00

AC:

AN:

37054

South Asian (SAS)

AF:

0.00

AC:

AN:

76274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1063630

Other (OTH)

AF:

0.00

AC:

AN:

56880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0019

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

7.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.57

REVEL

Benign

0.050

Sift

Benign

0.25

Sift4G

Benign

0.20

Polyphen

0.49

Vest4

0.42

MutPred

0.19

Gain of MoRF binding (P = 0.2168);

MVP

0.68

MPC

0.17

ClinPred

0.89

GERP RS

5.3

Varity_R

0.19

gMVP

0.51

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over