19-43625158-G-A

Position:

• chr19-43625158-G-A

Variant summary

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

The NM_145296.2(CADM4):​c.848C>T​(p.Ser283Phe) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CADM4 NM_145296.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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]

CADM4 (HGNC:):

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=0.423455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADM4	NM_145296.2	c.848C>T	p.Ser283Phe	missense_variant	7/9	ENST00000222374.3	NP_660339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM4	ENST00000222374.3	c.848C>T	p.Ser283Phe	missense_variant	7/9	1	NM_145296.2	ENSP00000222374.1
CADM4	ENST00000593506.1	n.154C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

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

Jun 11, 2024

The c.848C>T (p.S283F) alteration is located in exon 7 (coding exon 7) of the CADM4 gene. This alteration results from a C to T substitution at nucleotide position 848, causing the serine (S) at amino acid position 283 to be replaced by a phenylalanine (F). 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	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.043	T
Eigen	Benign	0.076
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.62	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.072	T
Sift4G	Benign	0.089	T
Polyphen		0.91	P
Vest4		0.31
MutPred		0.76		Loss of glycosylation at S283 (P = 0.044);
MVP		0.32
MPC		1.3
ClinPred		0.62	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.68

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: rs1269813470; hg19: chr19-44129310;