chr3-111884649-C-T

Position:

• chr3-111884649-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134438.2(PHLDB2):​c.572C>T​(p.Pro191Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,170 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030333102).
• BP6: Variant 3-111884649-C-T is Benign according to our data. Variant chr3-111884649-C-T is described in ClinVar as [Benign]. Clinvar id is 791945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1709/152308) while in subpopulation AFR AF= 0.0383 (1591/41580). AF 95% confidence interval is 0.0367. There are 39 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHLDB2	NM_001134438.2	c.572C>T	p.Pro191Leu	missense_variant	2/18	ENST00000431670.7	NP_001127910.1
PHLDB2	NM_001134439.2	c.572C>T	p.Pro191Leu	missense_variant	2/18		NP_001127911.1
PHLDB2	NM_001134437.2	c.653C>T	p.Pro218Leu	missense_variant	3/18		NP_001127909.1
PHLDB2	NM_145753.2	c.572C>T	p.Pro191Leu	missense_variant	2/17		NP_665696.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHLDB2	ENST00000431670.7	c.572C>T	p.Pro191Leu	missense_variant	2/18	1	NM_001134438.2	ENSP00000405405.2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1708 AN: 152190 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00294 AC: 737 AN: 250690 Hom.: 9 AF XY: 0.00207 AC XY: 280 AN XY: 135488

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00119 AC: 1733 AN: 1461862 Hom.: 29 Cov.: 33 AF XY: 0.00101 AC XY: 734 AN XY: 727228

Gnomad4 AFR exome AF: 0.0386

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.0112 AC: 1709 AN: 152308 Hom.: 39 Cov.: 32 AF XY: 0.0107 AC XY: 796 AN XY: 74466

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00134 Hom.: 3

Bravo AF: 0.0126

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00354 AC: 430

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.0
DANN	Benign	0.78
DEOGEN2	Benign	0.0054	.;.;T;T;.;T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T;T;.;T;T;T;T;.
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;L;L;.;.;.;L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.59	N;N;N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.15	T;T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T
Polyphen		0.0090	B;B;B;.;P;B;B;B
Vest4		0.23
MVP		0.41
MPC		0.093
ClinPred		0.0049	T
GERP RS		3.6
Varity_R		0.028
gMVP		0.19

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

Other links and lift over

dbSNP: rs75357207; hg19: chr3-111603496;