8-97775935-C-G

Variant names:

• chr8-97775935-C-G
• rs959939906
• ENST00000445593.6:c.199C>G

Variant summary

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

The ENST00000445593.6(LAPTM4B):​c.199C>G​(p.Arg67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,467,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. R67C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: LAPTM4B ENST00000445593.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309

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

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=0.13393387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAPTM4B	NM_018407.6	c.-75C>G		5_prime_UTR_variant	Exon 1 of 7	ENST00000521545.7	NP_060877.4
LOC124901986	XR_007061020.1	n.-160G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAPTM4B	ENST00000445593.6	c.199C>G	p.Arg67Gly	missense_variant	Exon 1 of 7	1		ENSP00000402301.2
LAPTM4B	ENST00000619747.1	c.199C>G	p.Arg67Gly	missense_variant	Exon 1 of 7	1		ENSP00000482533.1
LAPTM4B	ENST00000521545	c.-75C>G		5_prime_UTR_variant	Exon 1 of 7	1	NM_018407.6	ENSP00000428409.1
LAPTM4B	ENST00000517924	c.-75C>G		5_prime_UTR_variant	Exon 1 of 5	5		ENSP00000429868.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151992 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000269 AC: 2 AN: 74216 Hom.: 0 AF XY: 0.0000232 AC XY: 1 AN XY: 43116

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: 0.000142

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 48 AN: 1315192 Hom.: 0 Cov.: 35 AF XY: 0.0000417 AC XY: 27 AN XY: 648142

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: 0.0000261

Gnomad4 NFE exome AF: 0.0000438

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152098 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.28	T;.
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.75	.;N
REVEL	Benign	0.021
Sift	Uncertain	0.0050	.;D
Sift4G	Benign	0.083	T;T
Vest4		0.23
MVP		0.45
MPC		0.89
ClinPred		0.23	T
GERP RS		2.2
Varity_R		0.11
gMVP		0.23

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: rs959939906; hg19: chr8-98788163;