Genetic Variant NM_207517.3:c.190-3T>C (chr15-83773520-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_207517.3(ADAMTSL3):c.190-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,612,916 control chromosomes in the GnomAD database, including 4,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 389 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3789 hom. )

Consequence

ADAMTSL3
NM_207517.3 splice_region, intron

Scores

Splicing: ADA: 0.00004424

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0100

Publications

10 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 15-83773520-T-C is Benign according to our data. Variant chr15-83773520-T-C is described in ClinVar as Benign. ClinVar VariationId is 1294088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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.190-3T>C		splice_region intron	N/A	NP_997400.2	P82987-1
	ADAMTSL3	NM_001301110.2		c.190-3T>C		splice_region 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.190-3T>C	splice_region intron	N/A	ENSP00000286744.5	P82987-1
ADAMTSL3	ENST00000567476.1	TSL:1	c.190-3T>C	splice_region intron	N/A	ENSP00000456313.1	P82987-2
ADAMTSL3	ENST00000963409.1		c.190-3T>C	splice_region intron	N/A	ENSP00000633468.1

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9581

AN:

151970

Hom.:

386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0469

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0311

Gnomad ASJ

AF:

0.0465

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.0799

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0640

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0698

AC:

17508

AN:

250854

AF XY:

0.0707

show subpopulations

Gnomad AFR exome

AF:

0.0474

Gnomad AMR exome

AF:

0.0226

Gnomad ASJ exome

AF:

0.0426

Gnomad EAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.0638

Gnomad OTH exome

AF:

0.0616

GnomAD4 exome

AF:

0.0661

AC:

96529

AN:

1460826

Hom.:

3789

Cov.:

AF XY:

0.0663

AC XY:

48161

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.0474

AC:

1586

AN:

33438

American (AMR)

AF:

0.0230

AC:

1029

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0451

AC:

1176

AN:

26100

East Asian (EAS)

AF:

0.194

AC:

7670

AN:

39594

South Asian (SAS)

AF:

0.0763

AC:

6583

AN:

86224

European-Finnish (FIN)

AF:

0.111

AC:

5948

AN:

53352

Middle Eastern (MID)

AF:

0.0332

AC:

191

AN:

5756

European-Non Finnish (NFE)

AF:

0.0615

AC:

68393

AN:

1111340

Other (OTH)

AF:

0.0655

AC:

3953

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

4493

8986

13479

17972

22465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2568

5136

7704

10272

12840

<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:

0.0631

AC:

9591

AN:

152090

Hom.:

389

Cov.:

AF XY:

0.0645

AC XY:

4797

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0469

AC:

1948

AN:

41518

American (AMR)

AF:

0.0310

AC:

474

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0465

AC:

161

AN:

3466

East Asian (EAS)

AF:

0.183

AC:

947

AN:

5176

South Asian (SAS)

AF:

0.0806

AC:

388

AN:

4812

European-Finnish (FIN)

AF:

0.110

AC:

1159

AN:

10560

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0640

AC:

4348

AN:

67958

Other (OTH)

AF:

0.0535

AC:

113

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

436

872

1308

1744

2180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0605

Hom.:

226

Bravo

AF:

0.0564

Asia WGS

AF:

0.118

AC:

412

AN:

3478

EpiCase

AF:

0.0568

EpiControl

AF:

0.0570

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.5

(source)

DANN

Benign

0.82

PhyloP100

-0.010

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0

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