chr3-111884710-G-A

Position:

chr3-111884710-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134438.2(PHLDB2):c.633G>A(p.Met211Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

PHLDB2
NM_001134438.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.74

Variant links:

Genes affected

PHLDB2 (HGNC:29573): (pleckstrin homology like domain family B member 2) Enables cadherin binding activity. Involved in several processes, including negative regulation of focal adhesion assembly; regulation of cytoskeleton organization; and regulation of embryonic development. Located in several cellular components, including basal cortex; cell leading edge; and intermediate filament cytoskeleton. Colocalizes with focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

PHLDB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036693692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHLDB2	NM_001134438.2 linkuse as main transcript	c.633G>A	p.Met211Ile	missense_variant	2/18	ENST00000431670.7	NP_001127910.1	Q86SQ0-1
PHLDB2	NM_001134439.2 linkuse as main transcript	c.633G>A	p.Met211Ile	missense_variant	2/18		NP_001127911.1	Q86SQ0-1
PHLDB2	NM_001134437.2 linkuse as main transcript	c.714G>A	p.Met238Ile	missense_variant	3/18		NP_001127909.1	Q86SQ0-3
PHLDB2	NM_145753.2 linkuse as main transcript	c.633G>A	p.Met211Ile	missense_variant	2/17		NP_665696.1	Q86SQ0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHLDB2	ENST00000431670.7 linkuse as main transcript	c.633G>A	p.Met211Ile	missense_variant	2/18	1	NM_001134438.2	ENSP00000405405.2		Q86SQ0-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250808

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000118

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.633G>A (p.M211I) alteration is located in exon 2 (coding exon 1) of the PHLDB2 gene. This alteration results from a G to A substitution at nucleotide position 633, causing the methionine (M) at amino acid position 211 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0091

.;.;T;T;.;T;T;.

Eigen

Benign

-0.099

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.78

T;T;.;T;T;T;T;.

M_CAP

Benign

0.0072

MetaRNN

Benign

0.037

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

.;M;M;.;.;.;M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.82

N;N;N;N;N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.086

T;T;T;T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;.;B;B;B;B

Vest4

0.35

MutPred

0.16

.;Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);Gain of glycosylation at S212 (P = 0.0033);

MVP

0.51

MPC

0.10

ClinPred

0.11

GERP RS

4.7

Varity_R

0.29

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over