rs62637569

Positions:

• chr9-133536800-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014694.4(ADAMTSL2):​c.88A>G​(p.Thr30Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,182 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: ADAMTSL2 NM_014694.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004065
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0760

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027523935).
• BP6: Variant 9-133536800-A-G is Benign according to our data. Variant chr9-133536800-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235675.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1804/152344) while in subpopulation AFR AF= 0.0416 (1730/41578). AF 95% confidence interval is 0.04. There are 48 homozygotes in gnomad4. There are 872 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL2	NM_014694.4	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	2/19	ENST00000651351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	2/19		NM_014694.4	P1
ADAMTSL2	ENST00000393061.7	c.415A>G	p.Thr139Ala	missense_variant, splice_region_variant	2/19	1
ADAMTSL2	ENST00000354484.8	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	2/19	1		P1
ADAMTSL2	ENST00000393060.1	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	2/19	1		P1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1800 AN: 152226 Hom.: 48 Cov.: 34

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00325 AC: 815 AN: 250590 Hom.: 16 AF XY: 0.00253 AC XY: 343 AN XY: 135576

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00116 AC: 1697 AN: 1461838 Hom.: 29 Cov.: 33 AF XY: 0.00104 AC XY: 755 AN XY: 727220

Gnomad4 AFR exome AF: 0.0407

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.0118 AC: 1804 AN: 152344 Hom.: 48 Cov.: 34 AF XY: 0.0117 AC XY: 872 AN XY: 74506

Gnomad4 AFR AF: 0.0416

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00272 Hom.: 9

Bravo AF: 0.0130

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00404 AC: 490

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.9
DANN	Benign	0.93
DEOGEN2	Benign	0.012	T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.066
MVP		0.50
MPC		0.42
ClinPred		0.0015	T
GERP RS		1.8
Varity_R		0.032
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.16		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

Other links and lift over

dbSNP: rs62637569; hg19: chr9-136401922;