8-97775936-G-C

Variant names:

• chr8-97775936-G-C
• rs989041979
• ENST00000445593.6:c.200G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018407.6(LAPTM4B):​c.-74G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,469,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: LAPTM4B NM_018407.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.278
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08723083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAPTM4B	NM_018407.6	c.-74G>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000521545.7	NP_060877.4
LOC124901986	XR_007061020.1	n.-161C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAPTM4B	ENST00000445593.6	c.200G>C	p.Arg67Pro	missense_variant	Exon 1 of 7	1		ENSP00000402301.2
LAPTM4B	ENST00000619747.1	c.200G>C	p.Arg67Pro	missense_variant	Exon 1 of 7	1		ENSP00000482533.1
LAPTM4B	ENST00000521545.7	c.-74G>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_018407.6	ENSP00000428409.1
LAPTM4B	ENST00000517924.5	c.-74G>C		5_prime_UTR_variant	Exon 1 of 5	5		ENSP00000429868.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.0000134 AC: 1 AN: 74754 AF XY: 0.00

Gnomad AFR exome AF: 0.000526

Gnomad AMR exome AF: 0.00

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: 0.00000380 AC: 5 AN: 1317284 Hom.: 0 Cov.: 35 AF XY: 0.00000154 AC XY: 1 AN XY: 649380

African (AFR) AF: 0.000149 AC: 4 AN: 26782

American (AMR) AF: 0.00 AC: 0 AN: 22646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21928

East Asian (EAS) AF: 0.00 AC: 0 AN: 28916

South Asian (SAS) AF: 0.00 AC: 0 AN: 68820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4034

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051054

Other (OTH) AF: 0.0000183 AC: 1 AN: 54526

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152058 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74264

African (AFR) AF: 0.000193 AC: 8 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200G>C (p.R67P) alteration is located in exon 1 (coding exon 1) of the LAPTM4B gene. This alteration results from a G to C substitution at nucleotide position 200, causing the arginine (R) at amino acid position 67 to be replaced by a proline (P). 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	Benign	0.086
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.28	T;.
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.28
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.50	.;N
REVEL	Benign	0.0080
Sift	Uncertain	0.0050	.;D
Sift4G	Benign	0.23	T;T
Vest4		0.26
MVP		0.26
MPC		1.1
ClinPred		0.18	T
GERP RS		0.86
PromoterAI		0.061	Neutral
Varity_R		0.12
gMVP		0.22
Mutation Taster		=297/3	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: rs989041979; hg19: chr8-98788164;