4-127669126-G-A

Variant names:

• chr4-127669126-G-A
• rs1037828930
• NM_015693.4:c.1063G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015693.4(INTU):​c.1063G>A​(p.Glu355Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INTU NM_015693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTU	NM_015693.4	c.1063G>A	p.Glu355Lys	missense_variant	Exon 5 of 16	ENST00000335251.11	NP_056508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTU	ENST00000335251.11	c.1063G>A	p.Glu355Lys	missense_variant	Exon 5 of 16	1	NM_015693.4	ENSP00000334003.5
INTU	ENST00000503952.5	n.1063G>A		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000421995.1
INTU	ENST00000503626.5	n.1063G>A		non_coding_transcript_exon_variant	Exon 5 of 18	2		ENSP00000426287.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1386488 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 689844

African (AFR) AF: 0.00 AC: 0 AN: 31106

American (AMR) AF: 0.00 AC: 0 AN: 39908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24668

East Asian (EAS) AF: 0.00 AC: 0 AN: 37054

South Asian (SAS) AF: 0.00 AC: 0 AN: 76274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063628

Other (OTH) AF: 0.00 AC: 0 AN: 56880

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.066	T
Sift4G	Benign	0.068	T
Polyphen		0.69	P
Vest4		0.68
MutPred		0.36		Gain of ubiquitination at E355 (P = 0.0138);
MVP		0.68
MPC		0.23
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.62
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1037828930; hg19: chr4-128590281;