chr3-111884551-T-A

Position:

• chr3-111884551-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134438.2(PHLDB2):​c.474T>A​(p.His158Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090673506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHLDB2	NM_001134438.2	c.474T>A	p.His158Gln	missense_variant	2/18	ENST00000431670.7	NP_001127910.1
PHLDB2	NM_001134439.2	c.474T>A	p.His158Gln	missense_variant	2/18		NP_001127911.1
PHLDB2	NM_001134437.2	c.555T>A	p.His185Gln	missense_variant	3/18		NP_001127909.1
PHLDB2	NM_145753.2	c.474T>A	p.His158Gln	missense_variant	2/17		NP_665696.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHLDB2	ENST00000431670.7	c.474T>A	p.His158Gln	missense_variant	2/18	1	NM_001134438.2	ENSP00000405405.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.474T>A (p.H158Q) alteration is located in exon 2 (coding exon 1) of the PHLDB2 gene. This alteration results from a T to A substitution at nucleotide position 474, causing the histidine (H) at amino acid position 158 to be replaced by a glutamine (Q). 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	0.17
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.015
DANN	Benign	0.84
DEOGEN2	Benign	0.014	.;.;T;T;.;T;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T;T;.;T;T;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M;M;.;.;.;M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.23	T;T;T;T;T;T;T;T
Sift4G	Benign	0.82	T;T;T;T;D;T;T;T
Polyphen		0.10	B;B;P;.;D;B;P;B
Vest4		0.39
MutPred		0.18		.;Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);Gain of glycosylation at Y162 (P = 9e-04);
MVP		0.29
MPC		0.11
ClinPred		0.17	T
GERP RS		-6.1
Varity_R		0.028
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-111603398;