dbSNP rs769398487: CHADL:p.Arg761Leu (chr22-41229711-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_138481.2(CHADL):c.2282G>T(p.Arg761Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R761H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHADL
NM_138481.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.727

Publications

2 publications found

Variant links:

Genes affected

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:

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:

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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=0.08894655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138481.2. 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
	CHADL	NM_138481.2	MANE Select	c.2282G>T	p.Arg761Leu	missense	Exon 6 of 6	NP_612490.1	Q6NUI6-1
	L3MBTL2	NM_031488.5	MANE Select	c.2005+55C>A		intron	N/A	NP_113676.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHADL	ENST00000216241.14	TSL:1 MANE Select	c.2282G>T	p.Arg761Leu	missense	Exon 6 of 6	ENSP00000216241.9	Q6NUI6-1
L3MBTL2	ENST00000216237.10	TSL:1 MANE Select	c.2005+55C>A		intron	N/A	ENSP00000216237.5	Q969R5-1
L3MBTL2	ENST00000466589.5	TSL:1	n.2539+55C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250094

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460076

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.0000166

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.33

M_CAP

Benign

0.045

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-0.73

PrimateAI

Benign

0.21

PROVEAN

Benign

0.15

REVEL

Benign

0.060

Sift

Uncertain

0.024

Sift4G

Uncertain

0.037

Polyphen

0.18

Vest4

0.23

MutPred

0.49

Loss of MoRF binding (P = 5e-04)

MVP

0.20

MPC

0.026

ClinPred

0.17

GERP RS

0.15

Varity_R

0.061

gMVP

0.46

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over