22-41220782-A-G

Variant names:

• chr22-41220782-A-G
• rs1241156165
• NM_031488.5:c.767A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031488.5(L3MBTL2):​c.767A>G​(p.His256Arg) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H256L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: L3MBTL2 NM_031488.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

Genes affected

L3MBTL2 (HGNC:18594): (L3MBTL histone methyl-lysine binding protein 2) Enables methylated histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including ectoderm development; regulation of histone modification; and stem cell proliferation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

L3MBTL2-AS1 (HGNC:40847): (L3MBTL2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3850219).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031488.5. 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
	L3MBTL2	NM_031488.5	MANE Select	c.767A>G	p.His256Arg	missense	Exon 7 of 17	NP_113676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L3MBTL2	ENST00000216237.10	TSL:1 MANE Select	c.767A>G	p.His256Arg	missense	Exon 7 of 17	ENSP00000216237.5	Q969R5-1
	L3MBTL2	ENST00000466589.5	TSL:1	n.821A>G		non_coding_transcript_exon	Exon 7 of 16
	L3MBTL2	ENST00000892682.1		c.767A>G	p.His256Arg	missense	Exon 7 of 17	ENSP00000562741.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PhyloP100		2.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.14
Sift	Benign	0.67	T
Sift4G	Benign	0.75	T
Polyphen		0.018	B
Vest4		0.44
MutPred		0.60		Loss of catalytic residue at D253 (P = 0.1187)
MVP		0.62
MPC		0.45
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.36
gMVP		0.69
Mutation Taster		=65/35	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: rs1241156165; hg19: chr22-41616786;