rs542070490

Variant names:

• chr5-140786399-G-A
• NM_018900.4:c.109G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-140786399-G-A
• chr5-140786399-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018900.4(PCDHA1):​c.109G>A​(p.Glu37Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E37Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86

Genes affected

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

ENSG00000279726 (HGNC:):

PCDHA@ (HGNC:8662):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 1		NP_113598.1
PCDHA1	NM_031411.3	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 4		NP_113599.1
PCDHA@		n.140786399G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.3113C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	4.4	H;H;H
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.80
MutPred		0.92		Gain of methylation at E37 (P = 0.0106);Gain of methylation at E37 (P = 0.0106);Gain of methylation at E37 (P = 0.0106);
MVP		0.88
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.72
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140165984;