Genetic Variant L3MBTL3:p.Val114Ala (chr6-130051300-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032438.4(L3MBTL3):c.341T>C(p.Val114Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V114G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

L3MBTL3
NM_032438.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45

Publications

1 publications found

Variant links:

Genes affected

L3MBTL3 (HGNC:23035): (L3MBTL histone methyl-lysine binding protein 3) This gene encodes a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. Members of this family function as methyl-lysine readers, which recognize methylated lysine residues on histone protein tails, and are associated with the repression of gene expression. The encoded protein may regulate hematopoiesis. Homozygous deletion of this gene has been observed in human patients with medulloblastoma. [provided by RefSeq, Oct 2016]

L3MBTL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058814704).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032438.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L3MBTL3	NM_032438.4	MANE Select	c.341T>C	p.Val114Ala	missense	Exon 6 of 23	NP_115814.1	Q96JM7-1
L3MBTL3	NM_001007102.4		c.266T>C	p.Val89Ala	missense	Exon 5 of 22	NP_001007103.1	Q96JM7-2
L3MBTL3	NM_001346550.2		c.266T>C	p.Val89Ala	missense	Exon 5 of 22	NP_001333479.1	Q96JM7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L3MBTL3	ENST00000361794.7	TSL:5 MANE Select	c.341T>C	p.Val114Ala	missense	Exon 6 of 23	ENSP00000354526.2	Q96JM7-1
L3MBTL3	ENST00000533560.5	TSL:1	c.266T>C	p.Val89Ala	missense	Exon 5 of 22	ENSP00000437185.1	Q96JM7-2
L3MBTL3	ENST00000858931.1		c.446T>C	p.Val149Ala	missense	Exon 6 of 23	ENSP00000528990.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251392

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.060

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.64

M_CAP

Benign

0.0033

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

PhyloP100

1.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.23

REVEL

Benign

0.033

Sift

Benign

0.51

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.32

MutPred

0.41

Loss of sheet (P = 0.0054)

MVP

0.23

MPC

0.29

ClinPred

0.020

GERP RS

0.79

Varity_R

0.028

gMVP

0.17

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over