Genetic Variant NM_152750.5:c.326A>T (chr7-105981044-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152750.5(CDHR3):c.326A>T(p.Asp109Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDHR3
NM_152750.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

Publications

0 publications found

Variant links:

Genes affected

CDHR3 (HGNC:26308): (cadherin related family member 3) Predicted to enable cadherin binding activity and calcium ion binding activity. Predicted to be involved in calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules; cell morphogenesis; and cell-cell junction organization. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CDHR3 links:

ENSG00000307029 (HGNC:):

ENSG00000307029 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR3	NM_152750.5 link	c.326A>T	p.Asp109Val	missense_variant	Exon 3 of 19	ENST00000317716.14	NP_689963.2	Q6ZTQ4-1
CDHR3	NM_001301161.2 link	c.62A>T	p.Asp21Val	missense_variant	Exon 2 of 18		NP_001288090.1	Q6ZTQ4E7EQG5B7Z8X2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR3	ENST00000317716.14 link	c.326A>T	p.Asp109Val	missense_variant	Exon 3 of 19	1	NM_152750.5	ENSP00000325954.9		Q6ZTQ4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000809

AC:

AN:

247190

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

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:

0.00000205

AC:

AN:

1460698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726448

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.0000673

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111490

Other (OTH)

AF:

0.00

AC:

AN:

60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.326A>T (p.D109V) alteration is located in exon 3 (coding exon 3) of the CDHR3 gene. This alteration results from a A to T substitution at nucleotide position 326, causing the aspartic acid (D) at amino acid position 109 to be replaced by a valine (V). 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

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

T;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

6.0

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0080

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.72

MutPred

0.78

Gain of ubiquitination at K108 (P = 0.0557);.;

MVP

0.85

MPC

0.30

ClinPred

0.99

GERP RS

5.0

Varity_R

0.82

gMVP

0.76

Mutation Taster

=25/75

disease causing

(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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NM_152750.5:c.326A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over