5-140786609-G-A

Variant names:

• chr5-140786609-G-A
• rs782756413
• NM_018900.4:c.319G>A

Variant summary

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

The NM_018900.4(PCDHA1):​c.319G>A​(p.Glu107Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.687

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 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 rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 1		NP_113598.1
PCDHA1	NM_031411.3	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 4		NP_113599.1
PCDHA@		n.140786609G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.319G>A	p.Glu107Lys	missense_variant	Exon 1 of 1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.2903C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251476 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.319G>A (p.E107K) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a G to A substitution at nucleotide position 319, causing the glutamic acid (E) at amino acid position 107 to be replaced by a lysine (K). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;M;M
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.029	D;T;T
Polyphen		0.99	D;D;D
Vest4		0.29
MutPred		0.75		Gain of ubiquitination at E107 (P = 0.0211);Gain of ubiquitination at E107 (P = 0.0211);Gain of ubiquitination at E107 (P = 0.0211);
MVP		0.59
MPC		1.1
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.71
gMVP		0.54

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: rs782756413; hg19: chr5-140166194;