8-97775777-G-T

Variant names:

• chr8-97775777-G-T
• rs200565610
• ENST00000445593.6:c.41G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000445593.6(LAPTM4B):​c.41G>T​(p.Arg14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,557,676 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0073 (18 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (7 hom.)
• Consequence: LAPTM4B ENST00000445593.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 3 publications found

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]

LOC124901986 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030970871).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1082/147686) while in subpopulation AFR AF = 0.0243 (999/41182). AF 95% confidence interval is 0.023. There are 18 homozygotes in GnomAd4. There are 503 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAPTM4B	ENST00000445593.6	c.41G>T	p.Arg14Leu	missense_variant	Exon 1 of 7	1		ENSP00000402301.2
LAPTM4B	ENST00000619747.1	c.41G>T	p.Arg14Leu	missense_variant	Exon 1 of 7	1		ENSP00000482533.1
LAPTM4B	ENST00000521545.7	c.-233G>T		upstream_gene_variant		1	NM_018407.6	ENSP00000428409.1
LAPTM4B	ENST00000517924.5	c.-233G>T		upstream_gene_variant		5		ENSP00000429868.2

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 1079 AN: 147578 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00384

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000139

Gnomad OTH AF: 0.00783

GnomAD2 exomes AF: 0.00187 AC: 336 AN: 179914 AF XY: 0.00133

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000627

GnomAD4 exome AF: 0.000767 AC: 1082 AN: 1409990 Hom.: 7 Cov.: 39 AF XY: 0.000687 AC XY: 481 AN XY: 699982

African (AFR) AF: 0.0253 AC: 827 AN: 32670

American (AMR) AF: 0.00183 AC: 75 AN: 41032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25360

East Asian (EAS) AF: 0.00 AC: 0 AN: 37996

South Asian (SAS) AF: 0.0000954 AC: 8 AN: 83820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36182

Middle Eastern (MID) AF: 0.000819 AC: 4 AN: 4886

European-Non Finnish (NFE) AF: 0.0000569 AC: 62 AN: 1089474

Other (OTH) AF: 0.00181 AC: 106 AN: 58570

GnomAD4 genome AF: 0.00733 AC: 1082 AN: 147686 Hom.: 18 Cov.: 31 AF XY: 0.00696 AC XY: 503 AN XY: 72310

African (AFR) AF: 0.0243 AC: 999 AN: 41182

American (AMR) AF: 0.00383 AC: 57 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000139 AC: 9 AN: 64816

Other (OTH) AF: 0.00774 AC: 16 AN: 2066

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.00819

ExAC AF: 0.00172 AC: 192

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.31	T;.
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.028
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.57	.;N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.14	T;T
Vest4		0.16
MVP		0.41
MPC		0.36
ClinPred		0.039	T
GERP RS		2.9
PromoterAI		0.36	Neutral
Varity_R		0.16
gMVP		0.081
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs200565610; hg19: chr8-98788005;