22-41230150-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031488.5(L3MBTL2):c.2017C>T(p.Arg673Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000725 in 1,241,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict 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. R673H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

L3MBTL2
NM_031488.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Publications

3 publications found

Variant links:

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 links:

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]

CHADL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.07208061).

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.2017C>T	p.Arg673Cys	missense	Exon 17 of 17	NP_113676.2
	CHADL	NM_138481.2	MANE Select	c.2263-420G>A		intron	N/A	NP_612490.1	Q6NUI6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L3MBTL2	ENST00000216237.10	TSL:1 MANE Select	c.2017C>T	p.Arg673Cys	missense	Exon 17 of 17	ENSP00000216237.5	Q969R5-1
CHADL	ENST00000216241.14	TSL:1 MANE Select	c.2263-420G>A		intron	N/A	ENSP00000216241.9	Q6NUI6-1
L3MBTL2	ENST00000466589.5	TSL:1	n.2551C>T		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes

AF:

0.0000292

AC:

AN:

136864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250666

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000453

AC:

AN:

1104826

Hom.:

Cov.:

AF XY:

0.00000542

AC XY:

AN XY:

553574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24500

American (AMR)

AF:

0.0000529

AC:

AN:

37824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17020

East Asian (EAS)

AF:

0.00

AC:

AN:

18088

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4322

European-Non Finnish (NFE)

AF:

0.00000118

AC:

AN:

846554

Other (OTH)

AF:

0.0000242

AC:

AN:

41274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000292

AC:

AN:

136864

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

65588

show subpopulations

African (AFR)

AF:

0.0000266

AC:

AN:

37628

American (AMR)

AF:

0.000236

AC:

AN:

12692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3326

East Asian (EAS)

AF:

0.00

AC:

AN:

3924

South Asian (SAS)

AF:

0.00

AC:

AN:

3808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64492

Other (OTH)

AF:

0.00

AC:

AN:

1940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.051

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.76

M_CAP

Benign

0.0090

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.5

REVEL

Benign

0.034

Sift

Benign

0.056

Sift4G

Benign

0.099

Polyphen

0.0

Vest4

0.12

MutPred

0.46

Gain of sheet (P = 0.0477)

MVP

0.36

MPC

0.50

ClinPred

0.062

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.22

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over