Genetic Variant NM_006988.5:c.679G>C (chr21-26844276-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006988.5(ADAMTS1):c.679G>C(p.Ala227Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 1,599,118 control chromosomes in the GnomAD database, including 461,501 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.77 ( 46348 hom., cov: 33)

Exomes 𝑓: 0.75 ( 415153 hom. )

Consequence

ADAMTS1
NM_006988.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.102

Variant links:

Genes affected

ADAMTS1 (HGNC:217): (ADAM metallopeptidase with thrombospondin type 1 motif 1) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) 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 contains two disintegrin loops and three C-terminal TS motifs and has anti-angiogenic activity. The expression of this gene may be associated with various inflammatory processes as well as development of cancer cachexia. This gene is likely to be necessary for normal growth, fertility, and organ morphology and function. [provided by RefSeq, Jul 2008]

ADAMTS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.153148E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS1	NM_006988.5 link	c.679G>C	p.Ala227Pro	missense_variant	Exon 1 of 9	ENST00000284984.8	NP_008919.3	Q9UHI8B2RB33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS1	ENST00000284984.8 link	c.679G>C	p.Ala227Pro	missense_variant	Exon 1 of 9	1	NM_006988.5	ENSP00000284984.2	Q9UHI8
ADAMTS1	ENST00000676955.1 link	c.679G>C	p.Ala227Pro	missense_variant	Exon 1 of 8			ENSP00000503982.1	A0A7I2YQL5
ADAMTS1	ENST00000677958.1 link	n.679G>C		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000503777.1	A0A7I2V400
ADAMTS1	ENST00000679316.1 link	n.1134G>C		non_coding_transcript_exon_variant	Exon 1 of 7

Frequencies

GnomAD3 genomes

AF:

0.772

AC:

117356

AN:

152028

Hom.:

46294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.892

Gnomad AMI

AF:

0.680

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.761

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.695

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.770

Gnomad OTH

AF:

0.722

GnomAD3 exomes

AF:

0.703

AC:

162611

AN:

231396

Hom.:

59254

AF XY:

0.711

AC XY:

89517

AN XY:

125900

show subpopulations

Gnomad AFR exome

AF:

0.896

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.763

Gnomad EAS exome

AF:

0.432

Gnomad SAS exome

AF:

0.710

Gnomad FIN exome

AF:

0.792

Gnomad NFE exome

AF:

0.772

Gnomad OTH exome

AF:

0.719

GnomAD4 exome

AF:

0.753

AC:

1089855

AN:

1446972

Hom.:

415153

Cov.:

AF XY:

0.752

AC XY:

540191

AN XY:

718326

show subpopulations

Gnomad4 AFR exome

AF:

0.900

Gnomad4 AMR exome

AF:

0.474

Gnomad4 ASJ exome

AF:

0.755

Gnomad4 EAS exome

AF:

0.442

Gnomad4 SAS exome

AF:

0.708

Gnomad4 FIN exome

AF:

0.791

Gnomad4 NFE exome

AF:

0.773

Gnomad4 OTH exome

AF:

0.744

GnomAD4 genome

AF:

0.772

AC:

117462

AN:

152146

Hom.:

46348

Cov.:

AF XY:

0.767

AC XY:

57017

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.892

Gnomad4 AMR

AF:

0.593

Gnomad4 ASJ

AF:

0.761

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.695

Gnomad4 FIN

AF:

0.799

Gnomad4 NFE

AF:

0.770

Gnomad4 OTH

AF:

0.721

Alfa

AF:

0.764

Hom.:

10728

Bravo

AF:

0.755

TwinsUK

AF:

0.783

AC:

2905

ALSPAC

AF:

0.772

AC:

2976

ESP6500AA

AF:

0.891

AC:

3918

ESP6500EA

AF:

0.769

AC:

6604

ExAC

AF:

0.710

AC:

85823

Asia WGS

AF:

0.633

AC:

2201

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.6

DANN

Benign

0.86

DEOGEN2

Benign

0.083

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.33

MetaRNN

Benign

8.2e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.78

REVEL

Benign

0.040

Sift

Benign

0.27

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.025

MPC

0.32

ClinPred

0.0053

GERP RS

-0.15

Varity_R

0.064

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over