NM_001005473.3:c.407A>G

Variant names:

• chr5-41382231-T-C
• rs554578246
• NM_001005473.3:c.407A>G

Variant summary

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

The NM_001005473.3(PLCXD3):​c.407A>G​(p.His136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PLCXD3 NM_001005473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667
• Publications: 0 publications found

Genes affected

PLCXD3 (HGNC:31822): (phosphatidylinositol specific phospholipase C X domain containing 3) Predicted to enable phosphoric diester hydrolase activity. Predicted to be involved in lipid catabolic process and signal transduction. Predicted to be located in cytoplasm. Predicted to be active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

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=0.08918065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCXD3	NM_001005473.3	c.407A>G	p.His136Arg	missense_variant	Exon 2 of 3	ENST00000377801.8	NP_001005473.1
PLCXD3	XM_017009438.3	c.191A>G	p.His64Arg	missense_variant	Exon 2 of 3		XP_016864927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCXD3	ENST00000377801.8	c.407A>G	p.His136Arg	missense_variant	Exon 2 of 3	1	NM_001005473.3	ENSP00000367032.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250850 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461560 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 727080

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407A>G (p.H136R) alteration is located in exon 2 (coding exon 2) of the PLCXD3 gene. This alteration results from a A to G substitution at nucleotide position 407, causing the histidine (H) at amino acid position 136 to be replaced by an arginine (R). 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	0.045
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.54
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;N
PhyloP100		0.67
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.098
Sift	Benign	0.24	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.56		Loss of ubiquitination at K137 (P = 0.1121);Loss of ubiquitination at K137 (P = 0.1121);
MVP		0.16
MPC		0.11
ClinPred		0.049	T
GERP RS		0.67
Varity_R		0.065
gMVP		0.44
Mutation Taster		=80/20	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: rs554578246; hg19: chr5-41382333;