Variant 18-6138276-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001330559.2(L3MBTL4):c.1117C>A(p.Leu373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,610,766 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

L3MBTL4
NM_001330559.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.508

Variant links:

Genes affected

L3MBTL4 (HGNC:26677): (L3MBTL histone methyl-lysine binding protein 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

L3MBTL4 links:

L3MBTL4 (HGNC:):

L3MBTL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03197384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2 linkuse as main transcript	c.1117C>A	p.Leu373Ile	missense_variant	14/19	ENST00000317931.12	NP_001317488.1	F8W9S8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
L3MBTL4	ENST00000317931.12 linkuse as main transcript	c.1117C>A	p.Leu373Ile	missense_variant	14/19	5	NM_001330559.2	ENSP00000318543.7	F8W9S8
L3MBTL4	ENST00000400104.7 linkuse as main transcript	c.1117C>A	p.Leu373Ile	missense_variant	14/17	1		ENSP00000382975.3	Q8NA19-2
L3MBTL4	ENST00000400105.6 linkuse as main transcript	c.1117C>A	p.Leu373Ile	missense_variant	14/20	2		ENSP00000382976.2	Q8NA19-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

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:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000966

AC:

AN:

248402

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

134170

show subpopulations

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 SAS exome

AF:

0.000702

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000768

AC:

112

AN:

1458446

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

725468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000877

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.0000597

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.1117C>A (p.L373I) alteration is located in exon 14 (coding exon 12) of the L3MBTL4 gene. This alteration results from a C to A substitution at nucleotide position 1117, causing the leucine (L) at amino acid position 373 to be replaced by an isoleucine (I). 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

0.077

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.032

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

N;.;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.031

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.30

MutPred

0.41

Loss of catalytic residue at L373 (P = 0.0747);Loss of catalytic residue at L373 (P = 0.0747);Loss of catalytic residue at L373 (P = 0.0747);

MVP

0.32

ClinPred

0.027

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.12

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