20-9518097-A-T

Position:

• chr20-9518097-A-T

Variant summary

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

The NM_012261.4(LAMP5):​c.533A>T​(p.Lys178Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMP5 NM_012261.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.238

Genes affected

LAMP5 (HGNC:16097): (lysosomal associated membrane protein family member 5) Predicted to be involved in establishment of protein localization to organelle. Located in endoplasmic reticulum-Golgi intermediate compartment membrane; endosome membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.1170567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP5	NM_012261.4	c.533A>T	p.Lys178Met	missense_variant	5/6	ENST00000246070.3
LAMP5	NM_001199897.2	c.401A>T	p.Lys134Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP5	ENST00000246070.3	c.533A>T	p.Lys178Met	missense_variant	5/6	1	NM_012261.4	P1
LAMP5	ENST00000427562.6	c.401A>T	p.Lys134Met	missense_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.533A>T (p.K178M) alteration is located in exon 5 (coding exon 5) of the LAMP5 gene. This alteration results from a A to T substitution at nucleotide position 533, causing the lysine (K) at amino acid position 178 to be replaced by a methionine (M). 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N
MutationTaster	Benign	0.76	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.054
Sift	Benign	0.15	T;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0	B;B
Vest4		0.36
MutPred		0.53		.;Loss of ubiquitination at K178 (P = 0.0077);
MVP		0.076
MPC		0.077
ClinPred		0.18	T
GERP RS		1.0
Varity_R		0.17
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2045054604; hg19: chr20-9498744;