21-26844276-C-G

Variant names:

• chr21-26844276-C-G
• rs428785
• NM_006988.5:c.679G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant prognathism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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	c.679G>C	p.Ala227Pro	missense_variant	Exon 1 of 9	ENST00000284984.8	NP_008919.3

Ensembl

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

GnomAD2 exomes AF: 0.703 AC: 162611 AN: 231396 AF XY: 0.711

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 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

African (AFR) AF: 0.900 AC: 29901 AN: 33240

American (AMR) AF: 0.474 AC: 20328 AN: 42896

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 19260 AN: 25522

East Asian (EAS) AF: 0.442 AC: 17366 AN: 39290

South Asian (SAS) AF: 0.708 AC: 59427 AN: 83918

European-Finnish (FIN) AF: 0.791 AC: 40788 AN: 51560

Middle Eastern (MID) AF: 0.647 AC: 3661 AN: 5662

European-Non Finnish (NFE) AF: 0.773 AC: 854648 AN: 1105138

Other (OTH) AF: 0.744 AC: 44476 AN: 59746

GnomAD4 genome AF: 0.772 AC: 117462 AN: 152146 Hom.: 46348 Cov.: 33 AF XY: 0.767 AC XY: 57017 AN XY: 74366

African (AFR) AF: 0.892 AC: 37063 AN: 41566

American (AMR) AF: 0.593 AC: 9065 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2636 AN: 3466

East Asian (EAS) AF: 0.430 AC: 2188 AN: 5094

South Asian (SAS) AF: 0.695 AC: 3352 AN: 4820

European-Finnish (FIN) AF: 0.799 AC: 8475 AN: 10602

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.770 AC: 52356 AN: 67990

Other (OTH) AF: 0.721 AC: 1518 AN: 2106

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
PhyloP100		-0.10
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
PromoterAI		0.028	Neutral
Varity_R		0.064
gMVP		0.32
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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