Genetic Variant PHLDB3:p.Pro497Pro (chr19-43479588-T-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_198850.4(PHLDB3):c.1491A>C(p.Pro497Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 16)

Exomes 𝑓: 0.013 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

PHLDB3
NM_198850.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.46

Publications

7 publications found

Variant links:

Genes affected

PHLDB3 (HGNC:30499): (pleckstrin homology like domain family B member 3) Enables enzyme binding activity. [provided by Alliance of Genome Resources, Apr 2022]

PHLDB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 19-43479588-T-G is Benign according to our data. Variant chr19-43479588-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 791658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.46 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHLDB3	NM_198850.4 link	c.1491A>C	p.Pro497Pro	synonymous_variant	Exon 14 of 16	ENST00000292140.10	NP_942147.3	Q6NSJ2-1Q96HZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHLDB3	ENST00000292140.10 link	c.1491A>C	p.Pro497Pro	synonymous_variant	Exon 14 of 16	5	NM_198850.4	ENSP00000292140.5		Q6NSJ2-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

128610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00135

Gnomad AMR

AF:

0.000405

Gnomad ASJ

AF:

0.00102

Gnomad EAS

AF:

0.00140

Gnomad SAS

AF:

0.000267

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000310

Gnomad OTH

AF:

0.000579

GnomAD2 exomes

AF:

0.00738

AC:

897

AN:

121486

AF XY:

0.00727

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.00908

Gnomad ASJ exome

AF:

0.00410

Gnomad EAS exome

AF:

0.00756

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00610

Gnomad OTH exome

AF:

0.00951

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0134

AC:

6963

AN:

519244

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

3811

AN XY:

273318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0167

AC:

260

AN:

15536

American (AMR)

AF:

0.0195

AC:

562

AN:

28802

Ashkenazi Jewish (ASJ)

AF:

0.00863

AC:

143

AN:

16572

East Asian (EAS)

AF:

0.00846

AC:

241

AN:

28484

South Asian (SAS)

AF:

0.0269

AC:

1458

AN:

54194

European-Finnish (FIN)

AF:

0.00610

AC:

256

AN:

41954

Middle Eastern (MID)

AF:

0.00696

AC:

AN:

2012

European-Non Finnish (NFE)

AF:

0.0121

AC:

3691

AN:

305192

Other (OTH)

AF:

0.0128

AC:

338

AN:

26498

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

441

882

1324

1765

2206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.000381

AC:

AN:

128694

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

AN XY:

62234

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000386

AC:

AN:

36304

American (AMR)

AF:

0.000405

AC:

AN:

12352

Ashkenazi Jewish (ASJ)

AF:

0.00102

AC:

AN:

2948

East Asian (EAS)

AF:

0.00140

AC:

AN:

4280

South Asian (SAS)

AF:

0.000267

AC:

AN:

3742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.000310

AC:

AN:

58086

Other (OTH)

AF:

0.000574

AC:

AN:

1742

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.274

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:

0.00112

Hom.:

11581

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.90

(source)

DANN

Benign

0.42

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over