Genetic Variant L3MBTL2:p.Leu301Val (chr22-41221246-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031488.5(L3MBTL2):c.901C>G(p.Leu301Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,551,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00096 ( 1 hom. )

Consequence

L3MBTL2
NM_031488.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.277

Variant links:

Genes affected

L3MBTL2 (HGNC:18594): (L3MBTL histone methyl-lysine binding protein 2) Enables methylated histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including ectoderm development; regulation of histone modification; and stem cell proliferation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

L3MBTL2 links:

L3MBTL2-AS1 (HGNC:40847): (L3MBTL2 antisense RNA 1)

L3MBTL2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.082230985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L3MBTL2	NM_031488.5 link	c.901C>G	p.Leu301Val	missense_variant	Exon 8 of 17	ENST00000216237.10	NP_113676.2	Q969R5-1A0A0S2Z5X6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L3MBTL2	ENST00000216237.10 link	c.901C>G	p.Leu301Val	missense_variant	Exon 8 of 17	1	NM_031488.5	ENSP00000216237.5		Q969R5-1

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000981

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:

0.00128

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000818

AC:

130

AN:

158894

Hom.:

AF XY:

0.000910

AC XY:

AN XY:

83504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000591

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.000448

GnomAD4 exome

AF:

0.000956

AC:

1338

AN:

1399188

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

659

AN XY:

690034

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000983

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152378

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.000336

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.901C>G (p.L301V) alteration is located in exon 8 (coding exon 8) of the L3MBTL2 gene. This alteration results from a C to G substitution at nucleotide position 901, causing the leucine (L) at amino acid position 301 to be replaced by a valine (V). 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

0.77

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.26

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.66

Vest4

0.71

MVP

0.32

MPC

0.49

ClinPred

0.18

GERP RS

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over