7-105984200-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152750.5(CDHR3):c.424C>A(p.Leu142Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,450,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CDHR3 NM_152750.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.774

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29217103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR3	NM_152750.5	c.424C>A	p.Leu142Ile	missense_variant	4/19	ENST00000317716.14
CDHR3	NM_001301161.2	c.160C>A	p.Leu54Ile	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR3	ENST00000317716.14	c.424C>A	p.Leu142Ile	missense_variant	4/19	1	NM_152750.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245538 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000482 AC: 7 AN: 1450908 Hom.: 0 Cov.: 29 AF XY: 0.00000416 AC XY: 3 AN XY: 721180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.424C>A (p.L142I) alteration is located in exon 4 (coding exon 4) of the CDHR3 gene. This alteration results from a C to A substitution at nucleotide position 424, causing the leucine (L) at amino acid position 142 to be replaced by an isoleucine (I). 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	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	4.7
Dann	Benign	0.16
DEOGEN2	Benign	0.0010	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.15
Sift	Benign	0.58	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.78	P;.
Vest4		0.46
MutPred		0.49		Loss of sheet (P = 0.0817);.;
MVP		0.43
MPC		0.27
ClinPred		0.18	T
GERP RS		3.7
Varity_R		0.045
gMVP		0.089

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: rs775501689; hg19: chr7-105624646;