18-6093528-A-C

Position:

• chr18-6093528-A-C

Variant summary

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

The NM_001330559.2(L3MBTL4):​c.1200T>G​(p.Ser400Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: L3MBTL4 NM_001330559.2 missense, splice_region
• Scores: Splicing: ADA: 0.0009020
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0770

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]

L3MBTL4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	15/19	ENST00000317931.12	NP_001317488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	15/19	5	NM_001330559.2	ENSP00000318543.7
L3MBTL4	ENST00000400104.7	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	15/17	1		ENSP00000382975.3
L3MBTL4	ENST00000400105.6	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	15/20	2		ENSP00000382976.2
ENSG00000266846	ENST00000659442.1	n.1423+4178A>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458536 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Aug 02, 2024

The c.1200T>G (p.S400R) alteration is located in exon 15 (coding exon 13) of the L3MBTL4 gene. This alteration results from a T to G substitution at nucleotide position 1200, causing the serine (S) at amino acid position 400 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.90	D;T;D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.066	T;T;T
Sift4G	Benign	0.088	T;T;D
Polyphen		1.0	D;P;.
Vest4		0.54
MutPred		0.66		Loss of glycosylation at S400 (P = 0.0229);Loss of glycosylation at S400 (P = 0.0229);Loss of glycosylation at S400 (P = 0.0229);
MVP		0.48
ClinPred		0.94	D
GERP RS		1.5
Varity_R		0.25
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.41
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: chr18-6093527;