chr20-9529651-G-A

Position:

• chr20-9529651-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012261.4(LAMP5):​c.674G>A​(p.Cys225Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LAMP5 NM_012261.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP5	NM_012261.4	c.674G>A	p.Cys225Tyr	missense_variant	6/6	ENST00000246070.3
LAMP5	NM_001199897.2	c.542G>A	p.Cys181Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP5	ENST00000246070.3	c.674G>A	p.Cys225Tyr	missense_variant	6/6	1	NM_012261.4	P1
LAMP5	ENST00000427562.6	c.542G>A	p.Cys181Tyr	missense_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 05, 2022

The c.674G>A (p.C225Y) alteration is located in exon 6 (coding exon 6) of the LAMP5 gene. This alteration results from a G to A substitution at nucleotide position 674, causing the cysteine (C) at amino acid position 225 to be replaced by a tyrosine (Y). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.9	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.94		.;Loss of methylation at K224 (P = 0.0163);
MVP		0.48
MPC		0.45
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-9510298;