7-73831598-A-T

Variant names:

• chr7-73831598-A-T
• NM_001305.5:c.397A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001305.5(CLDN4):​c.397A>T​(p.Ile133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CLDN4 NM_001305.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389

Genes affected

CLDN4 (HGNC:2046): (claudin 4) The protein encoded by this intronless gene belongs to the claudin family. Claudins are integral membrane proteins that are components of the epithelial cell tight junctions, which regulate movement of solutes and ions through the paracellular space. This protein is a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) and may play a role in internal organ development and function during pre- and postnatal life. This gene is deleted in Williams-Beuren syndrome, a neurodevelopmental disorder affecting multiple systems. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06405583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN4	NM_001305.5	c.397A>T	p.Ile133Leu	missense_variant	Exon 1 of 1	ENST00000340958.4	NP_001296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN4	ENST00000340958.4	c.397A>T	p.Ile133Leu	missense_variant	Exon 1 of 1	6	NM_001305.5	ENSP00000342445.2
CLDN4	ENST00000431918.1	c.397A>T	p.Ile133Leu	missense_variant	Exon 2 of 2	2		ENSP00000388639.1
CLDN4	ENST00000435050.1	c.397A>T	p.Ile133Leu	missense_variant	Exon 2 of 2	2		ENSP00000409544.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.397A>T (p.I133L) alteration is located in exon 1 (coding exon 1) of the CLDN4 gene. This alteration results from a A to T substitution at nucleotide position 397, causing the isoleucine (I) at amino acid position 133 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.5
DANN	Benign	0.74
DEOGEN2	Benign	0.35	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.80	.;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.5	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.9	N;N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.065
MutPred		0.51		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.67
MPC		0.40
ClinPred		0.080	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73245928;