19-43639781-C-A

Variant names:

• chr19-43639781-C-A
• rs771204818
• NM_145296.2:c.10G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145296.2(CADM4):​c.10G>T​(p.Ala4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 871,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A4T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: CADM4 NM_145296.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

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]

ENSG00000308028 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066997886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145296.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM4	NM_145296.2	MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 1 of 9	NP_660339.1	Q8NFZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM4	ENST00000222374.3	TSL:1 MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 1 of 9	ENSP00000222374.1	Q8NFZ8
	CADM4	ENST00000904152.1		c.10G>T	p.Ala4Ser	missense	Exon 1 of 10	ENSP00000574211.1
	CADM4	ENST00000904153.1		c.10G>T	p.Ala4Ser	missense	Exon 1 of 9	ENSP00000574212.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 871436 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 411160

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

African (AFR) AF: 0.00 AC: 0 AN: 16350

American (AMR) AF: 0.00 AC: 0 AN: 4160

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 1 AN: 6344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4430

South Asian (SAS) AF: 0.00 AC: 0 AN: 22808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 785478

Other (OTH) AF: 0.00 AC: 0 AN: 28772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00073	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.023
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.030	B
Vest4		0.13
MutPred		0.37		Gain of phosphorylation at A4 (P = 0.023)
MVP		0.25
MPC		1.3
ClinPred		0.25	T
GERP RS		1.5
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.064
gMVP		0.28
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs771204818; hg19: chr19-44143933;