Genetic Variant ADAMTSL5:p.Arg388Cys (chr19-1506269-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_213604.3(ADAMTSL5):c.1162C>T(p.Arg388Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000282 in 1,561,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ADAMTSL5
NM_213604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.82

Publications

3 publications found

Variant links:

Genes affected

ADAMTSL5 (HGNC:27912): (ADAMTS like 5) Enables heparin binding activity and microfibril binding activity. Located in extracellular region and microfibril. [provided by Alliance of Genome Resources, Apr 2022]

ADAMTSL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12919807).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213604.3. 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
	ADAMTSL5	NM_213604.3	MANE Select	c.1162C>T	p.Arg388Cys	missense	Exon 12 of 12	NP_998769.2	X6R4H8
	ADAMTSL5	NM_001367197.1		c.1192C>T	p.Arg398Cys	missense	Exon 13 of 13	NP_001354126.1	Q6ZMM2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTSL5	ENST00000330475.9	TSL:2 MANE Select	c.1162C>T	p.Arg388Cys	missense	Exon 12 of 12	ENSP00000327608.3	X6R4H8
ADAMTSL5	ENST00000585700.5	TSL:1	n.1160C>T		non_coding_transcript_exon	Exon 11 of 11
ADAMTSL5	ENST00000590440.5	TSL:1	n.1200C>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000227

AC:

AN:

207306

AF XY:

0.000217

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.0000338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000283

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000419

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.000289

AC:

408

AN:

1409330

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

191

AN XY:

693938

show subpopulations

African (AFR)

AF:

0.0000616

AC:

AN:

32486

American (AMR)

AF:

0.0000248

AC:

AN:

40294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22692

East Asian (EAS)

AF:

0.000153

AC:

AN:

39134

South Asian (SAS)

AF:

0.00

AC:

AN:

77878

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.000352

AC:

381

AN:

1082530

Other (OTH)

AF:

0.000292

AC:

AN:

58146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000217

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000322

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000232

AC:

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

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0085

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.33

M_CAP

Benign

0.063

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

PhyloP100

3.8

PROVEAN

Benign

-0.040

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.21

MVP

0.70

ClinPred

0.35

GERP RS

3.5

Mutation Taster

=56/44

polymorphism

(source)

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

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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