20-43515051-C-A

Position:

• chr20-43515051-C-A

Variant summary

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

The NM_001377303.1(L3MBTL1):​c.545C>A​(p.Pro182His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: L3MBTL1 NM_001377303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.357

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=0.34347957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L3MBTL1	NM_001377303.1	c.545C>A	p.Pro182His	missense_variant	5/22	ENST00000418998.7	NP_001364232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L3MBTL1	ENST00000418998.7	c.545C>A	p.Pro182His	missense_variant	5/22	2	NM_001377303.1	ENSP00000398516.2
ENSG00000288000	ENST00000657241.1	c.1226C>A	p.Pro409His	missense_variant	9/26			ENSP00000499734.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 27, 2024

The c.479C>A (p.P160H) alteration is located in exon 5 (coding exon 4) of the L3MBTL1 gene. This alteration results from a C to A substitution at nucleotide position 479, causing the proline (P) at amino acid position 160 to be replaced by a histidine (H). 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	0.076
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;.;.;.;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Uncertain	2.1	.;.;.;.;M;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-8.4	D;.;N;.;D;N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;.;.;D;D
Polyphen		1.0	.;.;.;.;.;D;.
Vest4		0.28, 0.29, 0.28
MutPred		0.50		.;.;.;.;Loss of glycosylation at P92 (P = 0.0262);Loss of glycosylation at P92 (P = 0.0262);Loss of glycosylation at P92 (P = 0.0262);
MVP		0.80
MPC		0.55
ClinPred		0.95	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs2018309986; hg19: chr20-42143691; COSMIC: COSV64233986; COSMIC: COSV64233986;