NM_015344.3:c.146A>G

Variant names:

• chr8-30104353-A-G
• NM_015344.3:c.146A>G

Variant summary

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

The NM_015344.3(LEPROTL1):​c.146A>G​(p.Tyr49Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEPROTL1 NM_015344.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

Genes affected

LEPROTL1 (HGNC:6555): (leptin receptor overlapping transcript like 1) Enables identical protein binding activity. Predicted to be involved in late endosome to vacuole transport via multivesicular body sorting pathway and negative regulation of growth hormone receptor signaling pathway. Predicted to be integral component of membrane. Predicted to be active in endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROTL1	NM_015344.3	c.146A>G	p.Tyr49Cys	missense_variant	Exon 3 of 4	ENST00000321250.13	NP_056159.2
LEPROTL1	NM_001128208.2	c.146A>G	p.Tyr49Cys	missense_variant	Exon 3 of 4		NP_001121680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPROTL1	ENST00000321250.13	c.146A>G	p.Tyr49Cys	missense_variant	Exon 3 of 4	1	NM_015344.3	ENSP00000314625.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146A>G (p.Y49C) alteration is located in exon 3 (coding exon 3) of the LEPROTL1 gene. This alteration results from a A to G substitution at nucleotide position 146, causing the tyrosine (Y) at amino acid position 49 to be replaced by a cysteine (C). 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	0.11
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L;.;.;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.18	T;D;T;T;T
Polyphen		0.92	P;.;.;.;.
Vest4		0.78
MutPred		0.56		Gain of catalytic residue at P48 (P = 0.058);Gain of catalytic residue at P48 (P = 0.058);Gain of catalytic residue at P48 (P = 0.058);Gain of catalytic residue at P48 (P = 0.058);.;
MVP		0.28
MPC		1.8
ClinPred		0.99	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
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: chr8-29961869;