19-43479589-G-C

Position:

• chr19-43479589-G-C

Variant summary

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

The NM_198850.4(PHLDB3):​c.1490C>G​(p.Pro497Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P497L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHLDB3 NM_198850.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

Genes affected

PHLDB3 (HGNC:30499): (pleckstrin homology like domain family B member 3) Enables enzyme binding activity. [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=0.2197212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHLDB3	NM_198850.4	c.1490C>G	p.Pro497Arg	missense_variant	14/16	ENST00000292140.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHLDB3	ENST00000292140.10	c.1490C>G	p.Pro497Arg	missense_variant	14/16	5	NM_198850.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1345518 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 664362

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Nov 16, 2022

The c.1490C>G (p.P497R) alteration is located in exon 14 (coding exon 13) of the PHLDB3 gene. This alteration results from a C to G substitution at nucleotide position 1490, causing the proline (P) at amino acid position 497 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.73	N;.;.
MutationTaster	Benign	0.64	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.080	N;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D;.;.
Sift4G	Benign	0.087	T;T;T
Polyphen		0.59	P;.;.
Vest4		0.23
MutPred		0.24		Loss of glycosylation at P497 (P = 0.0056);.;.;
MVP		0.57
MPC		0.52
ClinPred		0.80	D
GERP RS		4.5
Varity_R		0.13
gMVP		0.54

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: rs538624470; hg19: chr19-43983741;