Genetic Variant NM_004361.5:c.476C>A (chr18-65809969-C-A) – 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_004361.5(CDH7):c.476C>A(p.Thr159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T159A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDH7
NM_004361.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.82

Publications

0 publications found

Variant links:

Genes affected

CDH7 (HGNC:1766): (cadherin 7) This gene encodes a type II classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium dependent cell-cell adhesion molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Type II (atypical) cadherins are defined based on their lack of a histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. Cadherins mediate cell-cell binding in a homophilic manner, contributing to the sorting of heterogeneous cell types. Mutations in this gene may be associated with bipolar disease in human patients. This gene is present in a gene cluster on chromosome 18. [provided by RefSeq, May 2016]

CDH7 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=0.28788114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH7	NM_004361.5 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 12	ENST00000397968.4	NP_004352.2	Q9ULB5
CDH7	NM_001362438.2 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 12		NP_001349367.1
CDH7	NM_033646.4 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 12		NP_387450.1	Q9ULB5
CDH7	NM_001317214.3 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 11		NP_001304143.1	Q9ULB5F5H5X9Q8IY78

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH7	ENST00000397968.4 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 12	1	NM_004361.5	ENSP00000381058.2	Q9ULB5
CDH7	ENST00000323011.7 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 12	1		ENSP00000319166.3	Q9ULB5
CDH7	ENST00000536984.6 link	c.476C>A	p.Thr159Lys	missense_variant	Exon 3 of 11	1		ENSP00000443030.2	F5H5X9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250284

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459676

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110080

Other (OTH)

AF:

0.00

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.074

T;T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.0066

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

N;.;N

PhyloP100

1.8

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.47

P;P;P

Vest4

0.56

MutPred

0.44

Gain of ubiquitination at T159 (P = 0.0247);Gain of ubiquitination at T159 (P = 0.0247);Gain of ubiquitination at T159 (P = 0.0247);

MVP

0.59

MPC

0.47

ClinPred

0.26

GERP RS

5.8

Varity_R

0.17

gMVP

0.37

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over