rs428785

Positions:

• chr21-26844276-C-G
• chr21-26844276-C-T
• chr21-26844276-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (46348 hom., cov: 33)
  • Exomes 𝑓: 0.75 (415153 hom.)
• Consequence: ADAMTS1 NM_006988.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102

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]

ACMG classification

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/exons	MANE	UniProt
ADAMTS1	NM_006988.5	c.679G>C	p.Ala227Pro	missense_variant	1/9	ENST00000284984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS1	ENST00000284984.8	c.679G>C	p.Ala227Pro	missense_variant	1/9	1	NM_006988.5	P1
ADAMTS1	ENST00000676955.1	c.679G>C	p.Ala227Pro	missense_variant	1/8
ADAMTS1	ENST00000679316.1	n.1134G>C		non_coding_transcript_exon_variant	1/7
ADAMTS1	ENST00000677958.1	c.679G>C	p.Ala227Pro	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117356 AN: 152028 Hom.: 46294 Cov.: 33

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

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.: 69 AF XY: 0.752 AC XY: 540191 AN XY: 718326

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.: 33 AF XY: 0.767 AC XY: 57017 AN XY: 74366

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	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.6
DANN	Benign	0.86
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.040
Sift	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.32
ClinPred		0.0053	T
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

Other links and lift over

dbSNP: rs428785; hg19: chr21-28216595; COSMIC: COSV53168606; COSMIC: COSV53168606;