3-111884453-G-A

Variant names:

• chr3-111884453-G-A
• rs2066075530
• NM_001134438.2:c.376G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001134438.2(PHLDB2):​c.376G>A​(p.Ala126Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.686

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 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=0.05687374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHLDB2	NM_001134438.2	c.376G>A	p.Ala126Thr	missense_variant	Exon 2 of 18	ENST00000431670.7	NP_001127910.1
PHLDB2	NM_001134439.2	c.376G>A	p.Ala126Thr	missense_variant	Exon 2 of 18		NP_001127911.1
PHLDB2	NM_001134437.2	c.457G>A	p.Ala153Thr	missense_variant	Exon 3 of 18		NP_001127909.1
PHLDB2	NM_145753.2	c.376G>A	p.Ala126Thr	missense_variant	Exon 2 of 17		NP_665696.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHLDB2	ENST00000431670.7	c.376G>A	p.Ala126Thr	missense_variant	Exon 2 of 18	1	NM_001134438.2	ENSP00000405405.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>A (p.A126T) 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 376, causing the alanine (A) at amino acid position 126 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.78
DEOGEN2	Benign	0.0045	.;.;T;T;.;T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T;T;.;T;T;T;T;.
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;L;.;.;.;L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.10	N;N;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.32	T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;B;B
Vest4		0.16
MutPred		0.15		.;Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);Gain of glycosylation at Y131 (P = 0.0019);
MVP		0.40
MPC		0.089
ClinPred		0.11	T
GERP RS		0.93
Varity_R		0.015
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

Other links and lift over

dbSNP: rs2066075530; hg19: chr3-111603300;