Genetic Variant NM_153021.5:c.414T>C (chr2-28529405-T-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_153021.5(PLB1):c.414T>C(p.Ala138Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,594,000 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00078 ( 6 hom. )

Consequence

PLB1
NM_153021.5 splice_region, synonymous

Scores

Splicing: ADA: 0.00002612

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.369

Publications

0 publications found

Variant links:

Genes affected

PLB1 (HGNC:30041): (phospholipase B1) This gene encodes a membrane-associated phospholipase that displays lysophospholipase and phospholipase A2 activities through removal of sn-1 and sn-2 fatty acids of glycerophospholipids. In addition, it displays lipase and retinyl ester hydrolase activities. The encoded protein is highly conserved and is composed of a large, glycosylated extracellular domain composed of four tandem homologous domains, followed by a hydrophobic segment that anchors the enzyme to the membrane and a short C-terminal cytoplasmic tail. This gene has been identified as a candidate rheumatoid arthritis risk gene. [provided by RefSeq, Jul 2016]

PLB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.131).

BP6

Variant 2-28529405-T-C is Benign according to our data. Variant chr2-28529405-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 728995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.369 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153021.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLB1	NM_153021.5	MANE Select	c.414T>C	p.Ala138Ala	splice_region synonymous	Exon 7 of 58	NP_694566.4
	PLB1	NM_001170585.2		c.414T>C	p.Ala138Ala	splice_region synonymous	Exon 7 of 57	NP_001164056.1	Q6P1J6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLB1	ENST00000327757.10	TSL:1 MANE Select	c.414T>C	p.Ala138Ala	splice_region synonymous	Exon 7 of 58	ENSP00000330442.5	Q6P1J6-1
PLB1	ENST00000422425.6	TSL:1	c.414T>C	p.Ala138Ala	splice_region synonymous	Exon 7 of 57	ENSP00000416440.2	Q6P1J6-3
PLB1	ENST00000404858.5	TSL:1	c.408T>C	p.Ala136Ala	splice_region synonymous	Exon 7 of 57	ENSP00000384187.1	H7BYX7

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

338

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00117

AC:

294

AN:

251338

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000792

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000780

AC:

1125

AN:

1441690

Hom.:

Cov.:

AF XY:

0.000782

AC XY:

562

AN XY:

718456

show subpopulations

African (AFR)

AF:

0.00479

AC:

158

AN:

32996

American (AMR)

AF:

0.00242

AC:

108

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.000845

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.0000699

AC:

AN:

85800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00592

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000630

AC:

689

AN:

1093690

Other (OTH)

AF:

0.00181

AC:

108

AN:

59784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152310

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00539

AC:

224

AN:

41560

American (AMR)

AF:

0.00373

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68022

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00284

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.98

(source)

DANN

Benign

0.16

PhyloP100

-0.37

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over