18-6213164-A-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.966T>G(p.Asp322Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414

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=0.0999659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL4	NM_001330559.2	c.966T>G	p.Asp322Glu	missense_variant	12/19	ENST00000317931.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.966T>G	p.Asp322Glu	missense_variant	12/19	5	NM_001330559.2	P4
L3MBTL4	ENST00000400104.7	c.966T>G	p.Asp322Glu	missense_variant	12/17	1
L3MBTL4	ENST00000400105.6	c.966T>G	p.Asp322Glu	missense_variant	12/20	2		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

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

Dec 07, 2023

The c.966T>G (p.D322E) alteration is located in exon 12 (coding exon 10) of the L3MBTL4 gene. This alteration results from a T to G substitution at nucleotide position 966, causing the aspartic acid (D) at amino acid position 322 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	12
Dann	Benign	0.83
DEOGEN2	Benign	0.016	T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N;.;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.77	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.032	B;B;.
Vest4		0.15
MutPred		0.27		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.25
ClinPred		0.17	T
GERP RS		-0.27
Varity_R		0.040
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: chr18-6213163;