6-130052957-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032438.4(L3MBTL3):c.548C>A(p.Thr183Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,611,926 control chromosomes in the GnomAD database, including 346,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.54 (25359 hom., cov: 32)
  • Exomes 𝑓: 0.66 (320775 hom.)
• Consequence: L3MBTL3 NM_032438.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.322221E-6).
• BP6: Variant 6-130052957-C-A is Benign according to our data. Variant chr6-130052957-C-A is described in ClinVar as [Benign]. Clinvar id is 1266479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL3	NM_032438.4	c.548C>A	p.Thr183Asn	missense_variant	7/23	ENST00000361794.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL3	ENST00000361794.7	c.548C>A	p.Thr183Asn	missense_variant	7/23	5	NM_032438.4	A1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81548 AN: 151840 Hom.: 25358 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.576

GnomAD3 exomes AF: 0.638 AC: 160163 AN: 250858 Hom.: 53251 AF XY: 0.644 AC XY: 87287 AN XY: 135630

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.769

Gnomad SAS exome AF: 0.595

Gnomad FIN exome AF: 0.669

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.658 AC: 959993 AN: 1459968 Hom.: 320775 Cov.: 39 AF XY: 0.657 AC XY: 477515 AN XY: 726340

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.655

Gnomad4 ASJ exome AF: 0.682

Gnomad4 EAS exome AF: 0.722

Gnomad4 SAS exome AF: 0.599

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.645

GnomAD4 genome AF: 0.537 AC: 81560 AN: 151958 Hom.: 25359 Cov.: 32 AF XY: 0.540 AC XY: 40106 AN XY: 74278

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.578

Alfa AF: 0.649 Hom.: 70716

Bravo AF: 0.523

TwinsUK AF: 0.673 AC: 2496

ALSPAC AF: 0.674 AC: 2596

ESP6500AA AF: 0.212 AC: 934

ESP6500EA AF: 0.681 AC: 5856

ExAC AF: 0.626 AC: 76036

Asia WGS AF: 0.644 AC: 2240 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2019

This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.077	T;T;.;T;.;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.58	D
MetaRNN	Benign	0.0000013	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;.;.;.;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N;N;N;N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.10	T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;B
Vest4		0.017
MPC		0.27
ClinPred		0.0066	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
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

Other links and lift over

dbSNP: rs9388768; hg19: chr6-130374102; COSMIC: COSV62384726; COSMIC: COSV62384726;