18-5969508-G-T

Variant names:

• chr18-5969508-G-T
• rs373941763
• NM_001330559.2:c.1499C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330559.2(L3MBTL4):​c.1499C>A​(p.Thr500Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T500M) has been classified as Uncertain significance.

• 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: 4.36
• 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]

ENSG00000266846 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09651518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2	c.1499C>A	p.Thr500Lys	missense_variant	Exon 17 of 19	ENST00000317931.12	NP_001317488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1499C>A	p.Thr500Lys	missense_variant	Exon 17 of 19	5	NM_001330559.2	ENSP00000318543.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60374

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	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	19
DANN	Benign	0.47
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.99	T
PhyloP100		4.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.079
Sift	Benign	0.29	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.025	B;B
Vest4		0.17
MutPred		0.40		Gain of ubiquitination at T509 (P = 0.0121);.;
MVP		0.25
ClinPred		0.81	D
GERP RS		3.7
Varity_R		0.077
gMVP		0.26
Mutation Taster		=84/16	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: rs373941763; hg19: chr18-5969507;