18-5956225-C-G

Variant names:

• chr18-5956225-C-G
• rs184790196
• NM_001330559.2:c.1840G>C

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.1840G>C​(p.Gly614Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• 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]

ENSG00000265487 (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=0.06238109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2	c.1840G>C	p.Gly614Arg	missense_variant	Exon 19 of 19	ENST00000317931.12	NP_001317488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1840G>C	p.Gly614Arg	missense_variant	Exon 19 of 19	5	NM_001330559.2	ENSP00000318543.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460210 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726336

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111340

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		0.34
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.020	B;B
Vest4		0.092
MutPred		0.29		Gain of solvent accessibility (P = 0.0037);.;
MVP		0.20
ClinPred		0.48	T
GERP RS		3.7
Varity_R		0.085
gMVP		0.20
Mutation Taster		=97/3	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: rs184790196; hg19: chr18-5956224;