18-6138234-T-C

Position:

• chr18-6138234-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330559.2(L3MBTL4):​c.1159A>G​(p.Ile387Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.303

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]

ACMG classification

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=0.111514896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL4	NM_001330559.2	c.1159A>G	p.Ile387Val	missense_variant	14/19	ENST00000317931.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1159A>G	p.Ile387Val	missense_variant	14/19	5	NM_001330559.2	P4
L3MBTL4	ENST00000400104.7	c.1159A>G	p.Ile387Val	missense_variant	14/17	1
L3MBTL4	ENST00000400105.6	c.1159A>G	p.Ile387Val	missense_variant	14/20	2		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.1159A>G (p.I387V) alteration is located in exon 14 (coding exon 12) of the L3MBTL4 gene. This alteration results from a A to G substitution at nucleotide position 1159, causing the isoleucine (I) at amino acid position 387 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	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.86	D;D;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.10	N;.;N
MutationTaster	Benign	0.92	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.031	B;B;.
Vest4		0.26
MutPred		0.36		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.24
ClinPred		0.39	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-6138233;