18-6138281-T-G

Variant summary

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

The NM_001330559.2(L3MBTL4):c.1112A>C(p.Lys371Thr) 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. 13/21 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: 3.21

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=0.2241725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL4	NM_001330559.2	c.1112A>C	p.Lys371Thr	missense_variant	14/19	ENST00000317931.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1112A>C	p.Lys371Thr	missense_variant	14/19	5	NM_001330559.2	P4
L3MBTL4	ENST00000400104.7	c.1112A>C	p.Lys371Thr	missense_variant	14/17	1
L3MBTL4	ENST00000400105.6	c.1112A>C	p.Lys371Thr	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

Feb 10, 2022

The c.1112A>C (p.K371T) alteration is located in exon 14 (coding exon 12) of the L3MBTL4 gene. This alteration results from a A to C substitution at nucleotide position 1112, causing the lysine (K) at amino acid position 371 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.077
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.89	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.27	B;B;.
Vest4		0.46
MutPred		0.46		Loss of ubiquitination at K371 (P = 0.0127);Loss of ubiquitination at K371 (P = 0.0127);Loss of ubiquitination at K371 (P = 0.0127);
MVP		0.29
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr18-6138280;