22-41221270-G-T

Variant names:

• chr22-41221270-G-T
• rs374138813
• NM_031488.5:c.925G>T

Variant summary

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

The NM_031488.5(L3MBTL2):​c.925G>T​(p.Val309Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V309M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: L3MBTL2 NM_031488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.196419).

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.925G>T	p.Val309Leu	missense	Exon 8 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.925G>T	p.Val309Leu	missense	Exon 8 of 17	ENSP00000216237.5	Q969R5-1
	L3MBTL2	ENST00000466589.5	TSL:1	n.979G>T		non_coding_transcript_exon	Exon 8 of 16
	L3MBTL2	ENST00000892682.1		c.925G>T	p.Val309Leu	missense	Exon 8 of 17	ENSP00000562741.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690088

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078838

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 34

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	Uncertain	0.53
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.010
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.082
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.0040	B
Vest4		0.36
MutPred		0.49		Loss of ubiquitination at K314 (P = 0.0896)
MVP		0.55
MPC		0.36
ClinPred		0.63	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.59
Mutation Taster		=84/16	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: rs374138813; hg19: chr22-41617274;