chr8-97816072-G-T

Variant names:

• chr8-97816072-G-T
• rs1816908189
• NM_018407.6:c.300G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018407.6(LAPTM4B):​c.300G>T​(p.Trp100Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LAPTM4B NM_018407.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAPTM4B	NM_018407.6	c.300G>T	p.Trp100Cys	missense_variant	Exon 4 of 7	ENST00000521545.7	NP_060877.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAPTM4B	ENST00000521545.7	c.300G>T	p.Trp100Cys	missense_variant	Exon 4 of 7	1	NM_018407.6	ENSP00000428409.1
LAPTM4B	ENST00000445593.6	c.573G>T	p.Trp191Cys	missense_variant	Exon 4 of 7	1		ENSP00000402301.2
LAPTM4B	ENST00000619747.1	c.573G>T	p.Trp191Cys	missense_variant	Exon 4 of 7	1		ENSP00000482533.1
LAPTM4B	ENST00000517924.5	c.324G>T	p.Trp108Cys	missense_variant	Exon 4 of 5	5		ENSP00000429868.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460600 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726540

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.573G>T (p.W191C) alteration is located in exon 4 (coding exon 4) of the LAPTM4B gene. This alteration results from a G to T substitution at nucleotide position 573, causing the tryptophan (W) at amino acid position 191 to be replaced by a cysteine (C). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.47	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.8	.;D;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Vest4		0.66
MVP		0.64
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1816908189; hg19: chr8-98828300;