5-140786430-G-T

Variant names:

• chr5-140786430-G-T
• NM_018900.4:c.140G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018900.4(PCDHA1):​c.140G>T​(p.Arg47Leu) 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 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 1		NP_113598.1
PCDHA1	NM_031411.3	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 4		NP_113599.1
PCDHA@		n.140786430G>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.3082C>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461082 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>T (p.R47L) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a G to T substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 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	0.28
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.0	M;M;M
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.52
MutPred		0.65		Loss of methylation at R47 (P = 0.0775);Loss of methylation at R47 (P = 0.0775);Loss of methylation at R47 (P = 0.0775);
MVP		0.48
MPC		0.89
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.67

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: chr5-140166015;