Genetic Variant ADAMTSL3:c.364-134_364-132delAAA (chr15-83819661-CAAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_207517.3(ADAMTSL3):c.364-134_364-132delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 490,962 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 0)

Exomes 𝑓: 0.073 ( 0 hom. )

Consequence

ADAMTSL3
NM_207517.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.436

Publications

0 publications found

Variant links:

Genes affected

ADAMTSL3 (HGNC:14633): (ADAMTS like 3) Predicted to be involved in extracellular matrix organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ADAMTSL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the SAS (0.108) population. However there is too low homozygotes in high coverage region: (expected more than 371, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207517.3. 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
	ADAMTSL3	NM_207517.3	MANE Select	c.364-134_364-132delAAA		intron	N/A	NP_997400.2	P82987-1
	ADAMTSL3	NM_001301110.2		c.364-134_364-132delAAA		intron	N/A	NP_001288039.1	P82987-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADAMTSL3	ENST00000286744.10	TSL:1 MANE Select	c.364-149_364-147delAAA	intron	N/A	ENSP00000286744.5	P82987-1
ADAMTSL3	ENST00000567476.1	TSL:1	c.364-149_364-147delAAA	intron	N/A	ENSP00000456313.1	P82987-2
ADAMTSL3	ENST00000963409.1		c.364-149_364-147delAAA	intron	N/A	ENSP00000633468.1

Frequencies

GnomAD3 genomes

AF:

0.000556

AC:

AN:

120432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000494

Gnomad ASJ

AF:

0.000338

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000703

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0727

AC:

26928

AN:

370576

Hom.:

AF XY:

0.0738

AC XY:

14337

AN XY:

194252

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0471

AC:

491

AN:

10424

American (AMR)

AF:

0.0743

AC:

1146

AN:

15430

Ashkenazi Jewish (ASJ)

AF:

0.0648

AC:

735

AN:

11350

East Asian (EAS)

AF:

0.0844

AC:

2165

AN:

25666

South Asian (SAS)

AF:

0.111

AC:

3814

AN:

34288

European-Finnish (FIN)

AF:

0.0644

AC:

1661

AN:

25784

Middle Eastern (MID)

AF:

0.0599

AC:

AN:

1636

European-Non Finnish (NFE)

AF:

0.0681

AC:

15283

AN:

224464

Other (OTH)

AF:

0.0713

AC:

1535

AN:

21534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.277

Heterozygous variant carriers

2427

4855

7282

9710

12137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

224

336

448

560

<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:

0.000557

AC:

AN:

120386

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

AN XY:

57128

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000125

AC:

AN:

32074

American (AMR)

AF:

0.000494

AC:

AN:

12154

Ashkenazi Jewish (ASJ)

AF:

0.000338

AC:

AN:

2962

East Asian (EAS)

AF:

0.00

AC:

AN:

4232

South Asian (SAS)

AF:

0.00

AC:

AN:

3530

European-Finnish (FIN)

AF:

0.00271

AC:

AN:

5904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.000703

AC:

AN:

56876

Other (OTH)

AF:

0.00

AC:

AN:

1642

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.44

Mutation Taster

=100/0

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