chr8-30101903-A-G

Variant names:

• chr8-30101903-A-G
• rs558458091
• NM_015344.3:c.22A>G

Variant summary

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

The NM_015344.3(LEPROTL1):​c.22A>G​(p.Ile8Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,599,966 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LEPROTL1 NM_015344.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89
• Publications: 1 publications found

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

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=0.12012896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015344.3. 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
	LEPROTL1	NM_015344.3	MANE Select	c.22A>G	p.Ile8Val	missense	Exon 2 of 4	NP_056159.2	O95214-1
	LEPROTL1	NM_001128208.2		c.22A>G	p.Ile8Val	missense	Exon 2 of 4	NP_001121680.1	O95214-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPROTL1	ENST00000321250.13	TSL:1 MANE Select	c.22A>G	p.Ile8Val	missense	Exon 2 of 4	ENSP00000314625.8	O95214-1
	LEPROTL1	ENST00000523116.5	TSL:2	c.22A>G	p.Ile8Val	missense	Exon 2 of 4	ENSP00000428281.1	O95214-2
	LEPROTL1	ENST00000520682.5	TSL:5	c.22A>G	p.Ile8Val	missense	Exon 2 of 4	ENSP00000429656.1	E5RHU8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248094 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

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: 6.91e-7 AC: 1 AN: 1447810 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720690

African (AFR) AF: 0.00 AC: 0 AN: 33146

American (AMR) AF: 0.00 AC: 0 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.00 AC: 0 AN: 84890

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102304

Other (OTH) AF: 0.00 AC: 0 AN: 59780

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

African (AFR) AF: 0.00 AC: 0 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.61		Loss of methylation at K5 (P = 0.1152)
MVP		0.13
MPC		0.53
ClinPred		0.36	T
GERP RS		5.8
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.58
Mutation Taster		=82/18	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: rs558458091; hg19: chr8-29959419; COSMIC: COSV58305045; COSMIC: COSV58305045;