19-43626168-G-A

Position:

• chr19-43626168-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145296.2(CADM4):​c.620C>T​(p.Pro207Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CADM4 NM_145296.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

CADM4 (HGNC:30825): (cell adhesion molecule 4) Enables vascular endothelial growth factor receptor 2 binding activity. Involved in several processes, including negative regulation of protein phosphorylation; regulation of Rac protein signal transduction; and regulation of wound healing. Located in cell leading edge and cell-cell contact zone. [provided by Alliance of Genome Resources, Apr 2022]

LOC105372411 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADM4	NM_145296.2	c.620C>T	p.Pro207Leu	missense_variant	5/9	ENST00000222374.3	NP_660339.1
LOC105372411	XR_001753942.2	n.573-2616G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM4	ENST00000222374.3	c.620C>T	p.Pro207Leu	missense_variant	5/9	1	NM_145296.2	ENSP00000222374	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 06, 2021

The c.620C>T (p.P207L) alteration is located in exon 5 (coding exon 5) of the CADM4 gene. This alteration results from a C to T substitution at nucleotide position 620, causing the proline (P) at amino acid position 207 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	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.47
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.40		Loss of disorder (P = 0.044);
MVP		0.80
MPC		2.1
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.17
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201258734; hg19: chr19-44130320;