21-26844276-C-A

Position:

• chr21-26844276-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006988.5(ADAMTS1):​c.679G>T​(p.Ala227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A227P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
  • Failed GnomAD Quality Control
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052804768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS1	NM_006988.5	c.679G>T	p.Ala227Ser	missense_variant	1/9	ENST00000284984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS1	ENST00000284984.8	c.679G>T	p.Ala227Ser	missense_variant	1/9	1	NM_006988.5	P1
ADAMTS1	ENST00000676955.1	c.679G>T	p.Ala227Ser	missense_variant	1/8
ADAMTS1	ENST00000679316.1	n.1134G>T		non_coding_transcript_exon_variant	1/7
ADAMTS1	ENST00000677958.1	c.679G>T	p.Ala227Ser	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000130 AC: 3 AN: 231396 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 125900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000715

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000176

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000760 AC: 11 AN: 1447218 Hom.: 0 Cov.: 69 AF XY: 0.0000111 AC XY: 8 AN XY: 718478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.9
DANN	Benign	0.79
DEOGEN2	Benign	0.056	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.022
Sift	Benign	0.73	T
Sift4G	Benign	0.71	T
Polyphen		0.0020	B
Vest4		0.097
MutPred		0.17		Gain of phosphorylation at A227 (P = 0.0176);
MVP		0.55
MPC		0.24
ClinPred		0.020	T
GERP RS		-0.15
Varity_R		0.025
gMVP		0.25

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;