Genetic Variant ENST00000354484.8:c.-648C>T (chr9-133532073-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000354484.8(ADAMTSL2):c.-648C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,418 control chromosomes in the GnomAD database, including 1,343 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1340 hom., cov: 33)

Exomes 𝑓: 0.20 ( 3 hom. )

Consequence

ADAMTSL2
ENST00000354484.8 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.590

Publications

1 publications found

Variant links:

Genes affected

ADAMTSL2 (HGNC:14631): (ADAMTS like 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia. [provided by RefSeq, Feb 2009]

ADAMTSL2 Gene-Disease associations (from GenCC):

geleophysic dysplasia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Ehlers-Danlos syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ADAMTSL2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000354484.8, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354484.8. 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
	ADAMTSL2	NM_001145320.2		c.-648C>T		upstream_gene	N/A	NP_001138792.1	Q86TH1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	ENST00000354484.8	TSL:1	c.-648C>T		upstream_gene	N/A	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18543

AN:

152174

Hom.:

1338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.0909

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.126

GnomAD4 exome

AF:

0.202

AC:

AN:

124

Hom.:

AF XY:

0.192

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0714

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.309

AC:

AN:

Other (OTH)

AF:

0.0625

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.122

AC:

18555

AN:

152294

Hom.:

1340

Cov.:

AF XY:

0.122

AC XY:

9099

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0578

AC:

2401

AN:

41566

American (AMR)

AF:

0.0909

AC:

1390

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

672

AN:

3470

East Asian (EAS)

AF:

0.166

AC:

859

AN:

5174

South Asian (SAS)

AF:

0.182

AC:

877

AN:

4830

European-Finnish (FIN)

AF:

0.133

AC:

1416

AN:

10614

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10404

AN:

68022

Other (OTH)

AF:

0.130

AC:

275

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

811

1622

2433

3244

4055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.133

Hom.:

972

Bravo

AF:

0.112

Asia WGS

AF:

0.156

AC:

542

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.0

(source)

DANN

Benign

0.62

PhyloP100

-0.59

PromoterAI

0.019

Neutral

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over