5-141331019-A-T

Variant names:

• chr5-141331019-A-T
• NM_018912.3:c.335A>T

Variant summary

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

The NM_018912.3(PCDHGA1):​c.335A>T​(p.Asp112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDHGA1 NM_018912.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

Genes affected

PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHG@ (HGNC:8695):

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
PCDHGA1	NM_018912.3	c.335A>T	p.Asp112Val	missense_variant	Exon 1 of 4	ENST00000517417.3	NP_061735.1
PCDHGA1	NM_031993.2	c.335A>T	p.Asp112Val	missense_variant	Exon 1 of 1		NP_114382.1
PCDHG@		n.141331019A>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHGA1	ENST00000517417.3	c.335A>T	p.Asp112Val	missense_variant	Exon 1 of 4	1	NM_018912.3	ENSP00000431083.1
PCDHGA1	ENST00000378105.4	c.335A>T	p.Asp112Val	missense_variant	Exon 1 of 1	6		ENSP00000367345.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335A>T (p.D112V) alteration is located in exon 1 (coding exon 1) of the PCDHGA1 gene. This alteration results from a A to T substitution at nucleotide position 335, causing the aspartic acid (D) at amino acid position 112 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.9	H;H
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.95	P;D
Vest4		0.32
MutPred		0.55		Gain of catalytic residue at D112 (P = 0.0633);Gain of catalytic residue at D112 (P = 0.0633);
MVP		0.71
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.60
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr5-140710586;