3-111884187-G-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.110G>A(p.Ser37Asn) 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 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • 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: 1.42

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=0.10904935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHLDB2	NM_001134438.2	c.110G>A	p.Ser37Asn	missense_variant	2/18	ENST00000431670.7
PHLDB2	NM_001134439.2	c.110G>A	p.Ser37Asn	missense_variant	2/18
PHLDB2	NM_001134437.2	c.191G>A	p.Ser64Asn	missense_variant	3/18
PHLDB2	NM_145753.2	c.110G>A	p.Ser37Asn	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHLDB2	ENST00000431670.7	c.110G>A	p.Ser37Asn	missense_variant	2/18	1	NM_001134438.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.110G>A (p.S37N) 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 110, causing the serine (S) at amino acid position 37 to be replaced by an asparagine (N). 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	-0.23	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T;T;.;T;T;T;T;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.18	T;T;T;T;T;T;T;T
Sift4G	Benign	0.074	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;B;B
Vest4		0.19
MutPred		0.15		.;Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);Gain of glycosylation at S39 (P = 0.0042);
MVP		0.45
MPC		0.086
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.39

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: rs1036976125; hg19: chr3-111603034;