8-97815346-C-T

Variant names:

• chr8-97815346-C-T
• rs777507821
• NM_018407.6:c.230C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018407.6(LAPTM4B):​c.230C>T​(p.Ala77Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A77E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LAPTM4B NM_018407.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55
• Publications: 2 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40509173).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018407.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAPTM4B	NM_018407.6	MANE Select	c.230C>T	p.Ala77Val	missense	Exon 3 of 7	NP_060877.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAPTM4B	ENST00000521545.7	TSL:1 MANE Select	c.230C>T	p.Ala77Val	missense	Exon 3 of 7	ENSP00000428409.1	Q86VI4-2
	LAPTM4B	ENST00000445593.6	TSL:1	c.503C>T	p.Ala168Val	missense	Exon 3 of 7	ENSP00000402301.2	Q86VI4-3
	LAPTM4B	ENST00000619747.1	TSL:1	c.503C>T	p.Ala168Val	missense	Exon 3 of 7	ENSP00000482533.1	Q86VI4-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251396 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727154

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74424

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41522

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.80	T
PhyloP100		4.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Uncertain	0.041	D
Vest4		0.53
MVP		0.47
MPC		0.37
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.80
Mutation Taster		=65/35	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: rs777507821; hg19: chr8-98827574; COSMIC: COSV71454081;