5-141331012-G-A

Variant names:

• chr5-141331012-G-A
• rs763935006
• NM_018912.3:c.328G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018912.3(PCDHGA1):​c.328G>A​(p.Val110Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. V110F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDHGA1 NM_018912.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.432
• Publications: 0 publications found

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]

ENSG00000294471 (HGNC:):

PCDHG@ (HGNC:8695):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072598755).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018912.3. 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
	PCDHGA1	NM_018912.3	MANE Select	c.328G>A	p.Val110Ile	missense	Exon 1 of 4	NP_061735.1	Q9Y5H4-1
	PCDHGA1	NM_031993.2		c.328G>A	p.Val110Ile	missense	Exon 1 of 1	NP_114382.1	Q9Y5H4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHGA1	ENST00000517417.3	TSL:1 MANE Select	c.328G>A	p.Val110Ile	missense	Exon 1 of 4	ENSP00000431083.1	Q9Y5H4-1
	PCDHGA1	ENST00000378105.4	TSL:6	c.328G>A	p.Val110Ile	missense	Exon 1 of 1	ENSP00000367345.3	Q9Y5H4-2
	ENSG00000294471	ENST00000723807.1		n.104C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.43
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.078
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.035	B
Vest4		0.19
MutPred		0.51		Loss of catalytic residue at V110 (P = 0.0171)
MVP		0.38
MPC		0.25
ClinPred		0.038	T
GERP RS		1.4
PromoterAI		0.013	Neutral
Varity_R		0.034
gMVP		0.039
Mutation Taster		=99/1	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: rs763935006; hg19: chr5-140710579;