dbSNP rs1418205234: PLBD1:p.Tyr375His (chr12-14511323-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_024829.6(PLBD1):c.1123T>C(p.Tyr375His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PLBD1
NM_024829.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11

Publications

0 publications found

Variant links:

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]

PLBD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLBD1	NM_024829.6 link	c.1123T>C	p.Tyr375His	missense_variant	Exon 8 of 11	ENST00000240617.10	NP_079105.4	Q6P4A8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLBD1	ENST00000240617.10 link	c.1123T>C	p.Tyr375His	missense_variant	Exon 8 of 11	1	NM_024829.6	ENSP00000240617.5	Q6P4A8
PLBD1	ENST00000541800.6 link	n.746T>C		non_coding_transcript_exon_variant	Exon 3 of 3	3
PLBD1	ENST00000541618.1 link	n.*890T>C		downstream_gene_variant		5		ENSP00000441278.1	F5GYQ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250926

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460244

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726504

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110764

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1123T>C (p.Y375H) alteration is located in exon 8 (coding exon 8) of the PLBD1 gene. This alteration results from a T to C substitution at nucleotide position 1123, causing the tyrosine (Y) at amino acid position 375 to be replaced by a histidine (H). 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

0.17

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PhyloP100

5.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.55

MutPred

0.64

Gain of disorder (P = 0.023);

MVP

0.26

MPC

0.86

ClinPred

0.99

GERP RS

6.1

Varity_R

0.55

gMVP

0.87

Mutation Taster

=86/14

polymorphism

(source)

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

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rs1418205234

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over