Genetic Variant ENST00000445593.6:c.41G>C (chr8-97775777-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000445593.6(LAPTM4B):c.41G>C(p.Arg14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000678 in 147,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LAPTM4B
ENST00000445593.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0280

Variant links:

Genes affected

LAPTM4B (HGNC:13646): (lysosomal protein transmembrane 4 beta) Enables ceramide binding activity; enzyme binding activity; and phosphatidylinositol bisphosphate binding activity. Involved in several processes, including negative regulation of macromolecule metabolic process; regulation of lysosomal membrane permeability; and regulation of lysosome organization. Located in several cellular components, including endosome; lysosomal membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LAPTM4B links:

LOC124901986 (HGNC:):

LOC124901986 links:

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ACMG classification

Classification made for transcript

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=0.1896593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAPTM4B	NM_018407.6 link	c.-233G>C		upstream_gene_variant		ENST00000521545.7	NP_060877.4	Q86VI4-2
LOC124901986	XR_007061020.1 link	n.-2C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAPTM4B	ENST00000445593.6 link	c.41G>C	p.Arg14Pro	missense_variant	Exon 1 of 7	1		ENSP00000402301.2	Q86VI4-3
LAPTM4B	ENST00000619747.1 link	c.41G>C	p.Arg14Pro	missense_variant	Exon 1 of 7	1		ENSP00000482533.1	Q86VI4-3
LAPTM4B	ENST00000521545.7 link	c.-233G>C		upstream_gene_variant		1	NM_018407.6	ENSP00000428409.1	Q86VI4-2
LAPTM4B	ENST00000517924.5 link	c.-233G>C		upstream_gene_variant		5		ENSP00000429868.2	H0YBN1

Frequencies

GnomAD3 genomes

AF:

0.00000678

AC:

AN:

147584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000154

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000222

AC:

AN:

179914

Hom.:

AF XY:

0.00

AC XY:

AN XY:

100550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000241

Gnomad NFE exome

AF:

0.0000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000128

AC:

AN:

1409588

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

699796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000244

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:

0.0000138

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.00000678

AC:

AN:

147584

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72196

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000154

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.27

T;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.76

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.31

.;N

REVEL

Benign

0.14

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.086

T;T

Vest4

0.30

MVP

0.48

MPC

0.41

ClinPred

0.49

GERP RS

2.9

Varity_R

0.25

gMVP

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over