18-6093379-T-A

Variant names:

• chr18-6093379-T-A
• rs2058521828
• NM_001330559.2:c.1349A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330559.2(L3MBTL4):​c.1349A>T​(p.His450Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.238
• Publications: 0 publications found

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]

ENSG00000266846 (HGNC:):

ACMG classification

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=0.06754866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2	c.1349A>T	p.His450Leu	missense_variant	Exon 15 of 19	ENST00000317931.12	NP_001317488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1349A>T	p.His450Leu	missense_variant	Exon 15 of 19	5	NM_001330559.2	ENSP00000318543.7
L3MBTL4	ENST00000400104.7	c.1349A>T	p.His450Leu	missense_variant	Exon 15 of 17	1		ENSP00000382975.3
L3MBTL4	ENST00000400105.6	c.1349A>T	p.His450Leu	missense_variant	Exon 15 of 20	2		ENSP00000382976.2
ENSG00000266846	ENST00000659442.1	n.1423+4029T>A		intron_variant	Intron 7 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1349A>T (p.H450L) alteration is located in exon 15 (coding exon 13) of the L3MBTL4 gene. This alteration results from a A to T substitution at nucleotide position 1349, causing the histidine (H) at amino acid position 450 to be replaced by a leucine (L). 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	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.7
DANN	Benign	0.67
DEOGEN2	Benign	0.015	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.41	N;.;N
PhyloP100		0.24
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.36
MutPred		0.23		Gain of MoRF binding (P = 0.1019);Gain of MoRF binding (P = 0.1019);Gain of MoRF binding (P = 0.1019);
MVP		0.16
ClinPred		0.098	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.35
Mutation Taster		=98/2	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: rs2058521828; hg19: chr18-6093378;