20-43515341-C-T

Position:

• chr20-43515341-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377303.1(L3MBTL1):​c.703C>T​(p.Leu235Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: L3MBTL1 NM_001377303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

L3MBTL1 (HGNC:15905): (L3MBTL histone methyl-lysine binding protein 1) This gene represents a polycomb group gene. The encoded protein functions to regulate gene activity, likely via chromatin modification. The encoded protein may also be necessary for mitosis. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

ENSG00000288000 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3338337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L3MBTL1	NM_001377303.1	c.703C>T	p.Leu235Phe	missense_variant	6/22	ENST00000418998.7	NP_001364232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L3MBTL1	ENST00000418998.7	c.703C>T	p.Leu235Phe	missense_variant	6/22	2	NM_001377303.1	ENSP00000398516.2
ENSG00000288000	ENST00000657241.1	c.1384C>T	p.Leu462Phe	missense_variant	10/26			ENSP00000499734.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429966 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 708520

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Jul 14, 2021

The c.637C>T (p.L213F) alteration is located in exon 6 (coding exon 5) of the L3MBTL1 gene. This alteration results from a C to T substitution at nucleotide position 637, causing the leucine (L) at amino acid position 213 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;.;.;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.86	D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	.;.;.;M;M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	.;N;.;.;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.26	.;T;.;.;D;D
Sift4G	Benign	0.14	.;T;.;.;T;T
Polyphen		0.96	.;.;.;.;D;.
Vest4		0.20, 0.21, 0.21
MutPred		0.21		.;.;.;Gain of methylation at K146 (P = 0.0307);Gain of methylation at K146 (P = 0.0307);Gain of methylation at K146 (P = 0.0307);
MVP		0.98
MPC		0.66
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2018333543; hg19: chr20-42143981;