6-130068341-G-C

Variant summary

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

The NM_032438.4(L3MBTL3):c.1012G>C(p.Glu338Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,432,648 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: 0.0000028 (0 hom.)
• Consequence: L3MBTL3 NM_032438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

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=0.22987685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL3	NM_032438.4	c.1012G>C	p.Glu338Gln	missense_variant	12/23	ENST00000361794.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL3	ENST00000361794.7	c.1012G>C	p.Glu338Gln	missense_variant	12/23	5	NM_032438.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1432648 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 714674

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: 0.00000368

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

Oct 25, 2023

The c.1012G>C (p.E338Q) alteration is located in exon 12 (coding exon 10) of the L3MBTL3 gene. This alteration results from a G to C substitution at nucleotide position 1012, causing the glutamic acid (E) at amino acid position 338 to be replaced by a glutamine (Q). 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	0.19
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.3	L;L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.051	T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.31	B;B;B;B;B;B
Vest4		0.29
MutPred		0.43		Loss of ubiquitination at K333 (P = 0.0604);Loss of ubiquitination at K333 (P = 0.0604);.;.;.;Loss of ubiquitination at K333 (P = 0.0604);
MVP		0.71
MPC		0.38
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr6-130389486;