rs150681845

Positions:

• chr4-127687772-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2
• Conservation: PhyloP100: 0.0190

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 504485.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTU	NM_015693.4	c.1354G>A	p.Ala452Thr	missense_variant	8/16	ENST00000335251.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTU	ENST00000335251.11	c.1354G>A	p.Ala452Thr	missense_variant	8/16	1	NM_015693.4	P1
INTU	ENST00000503952.5	c.*111G>A		3_prime_UTR_variant, NMD_transcript_variant	9/17	1
INTU	ENST00000503626.5	c.*2621G>A		3_prime_UTR_variant, NMD_transcript_variant	10/18	2
INTU	ENST00000506283.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152066 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00263 AC: 660 AN: 250842 Hom.: 3 AF XY: 0.00301 AC XY: 408 AN XY: 135544

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 SAS exome AF: 0.00912

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.: 17 Cov.: 30 AF XY: 0.00266 AC XY: 1932 AN XY: 726942

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00959

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152184 Hom.: 2 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74426

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 02, 2018	- -

Growth delay;C0687120:Nephronophthisis Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 09, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

INTU-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.1
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.0070
Sift	Benign	0.22	T
Sift4G	Benign	0.58	T
Polyphen		0.14	B
Vest4		0.14
MVP		0.081
MPC		0.11
ClinPred		0.0012	T
GERP RS		1.3
Varity_R		0.024
gMVP		0.53

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

Other links and lift over

dbSNP: rs150681845; hg19: chr4-128608927; COSMIC: COSV58872532; COSMIC: COSV58872532;