rs34575154

Positions:

• chr5-140787368-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018900.4(PCDHA1):​c.1078A>G​(p.Arg360Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,614,210 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (56 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026019514).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.1078A>G	p.Arg360Gly	missense_variant	1/4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.1078A>G	p.Arg360Gly	missense_variant	1/1		NP_113598.1
PCDHA1	NM_031411.3	c.1078A>G	p.Arg360Gly	missense_variant	1/4		NP_113599.1
PCDHA@		n.140787368A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.1078A>G	p.Arg360Gly	missense_variant	1/4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.1078A>G	p.Arg360Gly	missense_variant	1/4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.1078A>G	p.Arg360Gly	missense_variant	1/1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.2144T>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2314 AN: 152214 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00435 AC: 1095 AN: 251470 Hom.: 25 AF XY: 0.00319 AC XY: 434 AN XY: 135912

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00177 AC: 2582 AN: 1461878 Hom.: 56 Cov.: 32 AF XY: 0.00159 AC XY: 1156 AN XY: 727238

Gnomad4 AFR exome AF: 0.0576

Gnomad4 AMR exome AF: 0.00438

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.0153 AC: 2325 AN: 152332 Hom.: 64 Cov.: 33 AF XY: 0.0149 AC XY: 1112 AN XY: 74500

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00306 Hom.: 22

Bravo AF: 0.0175

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0513 AC: 226

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00517 AC: 628

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;L;L
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.073
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.76	P;B;P
Vest4		0.093
MVP		0.32
MPC		0.38
ClinPred		0.081	T
GERP RS		-1.1
Varity_R		0.29
gMVP		0.15

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: rs34575154; hg19: chr5-140166953;