6-130042725-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032438.4(L3MBTL3):c.26G>A(p.Ser9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: L3MBTL3 NM_032438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

Genes affected

L3MBTL3 (HGNC:23035): (L3MBTL histone methyl-lysine binding protein 3) This gene encodes a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. Members of this family function as methyl-lysine readers, which recognize methylated lysine residues on histone protein tails, and are associated with the repression of gene expression. The encoded protein may regulate hematopoiesis. Homozygous deletion of this gene has been observed in human patients with medulloblastoma. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12354326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL3	NM_032438.4	c.26G>A	p.Ser9Asn	missense_variant	3/23	ENST00000361794.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL3	ENST00000361794.7	c.26G>A	p.Ser9Asn	missense_variant	3/23	5	NM_032438.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251160 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460804 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726748

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Dec 12, 2023

The c.26G>A (p.S9N) alteration is located in exon 3 (coding exon 1) of the L3MBTL3 gene. This alteration results from a G to A substitution at nucleotide position 26, causing the serine (S) at amino acid position 9 to be replaced by an asparagine (N). 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	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.069	T;T;T;.;T;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.63	N;.;N;N;.;N;N;N
MutationTaster	Benign	0.66	N;N;N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.35	N;N;N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.23	T;T;T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;B;.;B;B;B
Vest4		0.096
MutPred		0.17		Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);Loss of glycosylation at S9 (P = 0.0201);
MVP		0.39
MPC		0.24
ClinPred		0.36	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.43

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: rs776070232; hg19: chr6-130363870;