rs145327462

Variant names:

• chr12-14503873-G-A
• rs145327462
• NM_024829.6:c.1561C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024829.6(PLBD1):​c.1561C>T​(p.Arg521Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PLBD1 NM_024829.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 1 publications found

Genes affected

PLBD1 (HGNC:26215): (phospholipase B domain containing 1) Predicted to enable phospholipase activity. Predicted to be involved in phospholipid catabolic process. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24231964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLBD1	NM_024829.6	c.1561C>T	p.Arg521Cys	missense_variant	Exon 11 of 11	ENST00000240617.10	NP_079105.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLBD1	ENST00000240617.10	c.1561C>T	p.Arg521Cys	missense_variant	Exon 11 of 11	1	NM_024829.6	ENSP00000240617.5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251364 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 160 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000109 AC: 121 AN: 1111824

Other (OTH) AF: 0.000166 AC: 10 AN: 60384

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74424

African (AFR) AF: 0.0000482 AC: 2 AN: 41530

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1561C>T (p.R521C) alteration is located in exon 11 (coding exon 11) of the PLBD1 gene. This alteration results from a C to T substitution at nucleotide position 1561, causing the arginine (R) at amino acid position 521 to be replaced by a cysteine (C). 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	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0023	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.070
Sift	Benign	0.041	D
Sift4G	Uncertain	0.052	T
Polyphen		0.98	D
Vest4		0.17
MVP		0.58
MPC		0.76
ClinPred		0.18	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.55
Mutation Taster		=95/5	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: rs145327462; hg19: chr12-14656807; COSMIC: COSV53693762; COSMIC: COSV53693762;