Genetic Variant CHADL:p.Asp671Asn (chr22-41236536-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138481.2(CHADL):c.2011G>A(p.Asp671Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,551,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

CHADL
NM_138481.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.1350438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHADL	NM_138481.2 link	c.2011G>A	p.Asp671Asn	missense_variant	Exon 4 of 6	ENST00000216241.14	NP_612490.1	Q6NUI6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHADL	ENST00000216241.14 link	c.2011G>A	p.Asp671Asn	missense_variant	Exon 4 of 6	1	NM_138481.2	ENSP00000216241.9	Q6NUI6-1
CHADL	ENST00000455425.1 link	c.502G>A	p.Asp168Asn	missense_variant	Exon 3 of 4	2		ENSP00000412359.1	B0QYT2
CHADL	ENST00000417999.5 link	c.1973+29G>A		intron_variant	Intron 3 of 4	5		ENSP00000392046.1	H0Y4I5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000844

AC:

AN:

153958

Hom.:

AF XY:

0.0000489

AC XY:

AN XY:

81732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000395

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000300

AC:

AN:

1399136

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

690070

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000202

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000139

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000246

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000337

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2011G>A (p.D671N) alteration is located in exon 4 (coding exon 4) of the CHADL gene. This alteration results from a G to A substitution at nucleotide position 2011, causing the aspartic acid (D) at amino acid position 671 to be replaced by an asparagine (N). 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

Benign

0.19

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0015

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.034

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

N;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.093

Sift

Benign

0.68

T;T

Sift4G

Benign

0.78

T;.

Polyphen

0.19

B;.

Vest4

0.18

MutPred

0.47

Gain of catalytic residue at D671 (P = 0.0112);.;

MVP

0.28

MPC

0.024

ClinPred

0.049

GERP RS

4.0

Varity_R

0.042

gMVP

0.54

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over