22-41230162-G-A

Position:

• chr22-41230162-G-A

Variant summary

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

The NM_031488.5(L3MBTL2):​c.2029G>A​(p.Glu677Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000725 in 1,378,666 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: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: L3MBTL2 NM_031488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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]

CHADL (HGNC:25165): (chondroadherin like) Enables collagen binding activity and collagen fibril binding activity. Involved in negative regulation of collagen fibril organization. Located in collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

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=0.153173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L3MBTL2	NM_031488.5	c.2029G>A	p.Glu677Lys	missense_variant	17/17	ENST00000216237.10	NP_113676.2
CHADL	NM_138481.2	c.2263-432C>T		intron_variant		ENST00000216241.14	NP_612490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L3MBTL2	ENST00000216237.10	c.2029G>A	p.Glu677Lys	missense_variant	17/17	1	NM_031488.5	ENSP00000216237	P1
CHADL	ENST00000216241.14	c.2263-432C>T		intron_variant		1	NM_138481.2	ENSP00000216241	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378666 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684354

Gnomad4 AFR exome AF: 0.0000322

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

Sep 22, 2022

The c.2029G>A (p.E677K) alteration is located in exon 17 (coding exon 17) of the L3MBTL2 gene. This alteration results from a G to A substitution at nucleotide position 2029, causing the glutamic acid (E) at amino acid position 677 to be replaced by a lysine (K). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.059	T
Polyphen		0.97	D
Vest4		0.40
MutPred		0.31		Gain of ubiquitination at E677 (P = 0.0025);
MVP		0.31
MPC		0.43
ClinPred		0.68	D
GERP RS		4.0
Varity_R		0.36
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555922213; hg19: chr22-41626166;