chr18-5956225-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001330559.2(L3MBTL4):​c.1840G>A​(p.Gly614Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,612,476 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.338
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03732723).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000197 AC: 49 AN: 248236 AF XY: 0.000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1460208 Hom.: 0 Cov.: 30 AF XY: 0.000329 AC XY: 239 AN XY: 726334

African (AFR) AF: 0.0000598 AC: 2 AN: 33442

American (AMR) AF: 0.0000449 AC: 2 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: 0.0000562 AC: 3 AN: 53402

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

European-Non Finnish (NFE) AF: 0.000428 AC: 476 AN: 1111338

Other (OTH) AF: 0.000464 AC: 28 AN: 60312

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74456

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.000218

EpiControl AF: 0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1867G>A (p.G623R) alteration is located in exon 20 (coding exon 18) of the L3MBTL4 gene. This alteration results from a G to A substitution at nucleotide position 1867, causing the glycine (G) at amino acid position 623 to be replaced by an arginine (R). 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	-0.52	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	0.10	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.037	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	0.049
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		0.15	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;