5-141854325-C-A

Position:

• chr5-141854325-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032420.5(PCDH1):​c.3431G>T​(p.Arg1144Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH1 NM_032420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

Genes affected

PCDH1 (HGNC:8655): (protocadherin 1) This gene belongs to the protocadherin subfamily within the cadherin superfamily. The encoded protein is a membrane protein found at cell-cell boundaries. It is involved in neural cell adhesion, suggesting a possible role in neuronal development. The protein includes an extracelllular region, containing 7 cadherin-like domains, a transmembrane region and a C-terminal cytoplasmic region. Cells expressing the protein showed cell aggregation activity. Alternative splicing occurs in this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38621178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5	c.3431G>T	p.Arg1144Leu	missense_variant	5/5	ENST00000287008.8	NP_115796.2
PCDH1	XM_005268452.4	c.3479G>T	p.Arg1160Leu	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3	c.2294G>T	p.Arg765Leu	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6	c.*125G>T		3_prime_UTR_variant	6/6		XP_005268511.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH1	ENST00000287008.8	c.3431G>T	p.Arg1144Leu	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3
PCDH1	ENST00000503492	c.*125G>T		3_prime_UTR_variant	5/5	5		ENSP00000424667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.3431G>T (p.R1144L) alteration is located in exon 5 (coding exon 5) of the PCDH1 gene. This alteration results from a G to T substitution at nucleotide position 3431, causing the arginine (R) at amino acid position 1144 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
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.68	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.090
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.53
MutPred		0.20		Loss of MoRF binding (P = 0.0228);
MVP		0.10
MPC		0.75
ClinPred		0.91	D
GERP RS		4.5
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr5-141233890;