rs150681845

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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:3

Conservation

PhyloP100: 0.0190

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 504485.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTU	NM_015693.4	MANE Select	c.1354G>A	p.Ala452Thr	missense	Exon 8 of 16	NP_056508.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INTU	ENST00000335251.11	TSL:1 MANE Select	c.1354G>A	p.Ala452Thr	missense	Exon 8 of 16	ENSP00000334003.5
INTU	ENST00000503952.5	TSL:1	n.*111G>A		non_coding_transcript_exon	Exon 9 of 17	ENSP00000421995.1
INTU	ENST00000503952.5	TSL:1	n.*111G>A		3_prime_UTR	Exon 9 of 17	ENSP00000421995.1

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

GnomAD2 exomes

AF:

0.00263

AC:

660

AN:

250842

AF XY:

0.00301

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33454

American (AMR)

AF:

0.00101

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00959

AC:

827

AN:

86196

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00215

AC:

2391

AN:

1111650

Other (OTH)

AF:

0.00280

AC:

169

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

164

328

493

657

821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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

AF:

0.00188

AC:

286

AN:

152184

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41514

American (AMR)

AF:

0.00419

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00767

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00218

AC:

148

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00195

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

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Growth delay;C0687120:Nephronophthisis (1)

INTU-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.1

(source)

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

PhyloP100

0.019

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

PromoterAI

-0.0091

Neutral

(source)

Varity_R

0.024

gMVP

0.53

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over