NM_032438.4:c.754A>C

Variant names:

• chr6-130057492-A-C
• rs1475686954
• NM_032438.4:c.754A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032438.4(L3MBTL3):​c.754A>C​(p.Lys252Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: L3MBTL3 NM_032438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18770343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032438.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L3MBTL3	NM_032438.4	MANE Select	c.754A>C	p.Lys252Gln	missense	Exon 9 of 23	NP_115814.1	Q96JM7-1
	L3MBTL3	NM_001007102.4		c.679A>C	p.Lys227Gln	missense	Exon 8 of 22	NP_001007103.1	Q96JM7-2
	L3MBTL3	NM_001346550.2		c.679A>C	p.Lys227Gln	missense	Exon 8 of 22	NP_001333479.1	Q96JM7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L3MBTL3	ENST00000361794.7	TSL:5 MANE Select	c.754A>C	p.Lys252Gln	missense	Exon 9 of 23	ENSP00000354526.2	Q96JM7-1
	L3MBTL3	ENST00000533560.5	TSL:1	c.679A>C	p.Lys227Gln	missense	Exon 8 of 22	ENSP00000437185.1	Q96JM7-2
	L3MBTL3	ENST00000858931.1		c.859A>C	p.Lys287Gln	missense	Exon 9 of 23	ENSP00000528990.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.54	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.40		Loss of methylation at K252 (P = 0.0024)
MVP		0.74
MPC		0.29
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.64
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1475686954; hg19: chr6-130378637;