9-18504940-C-T

Variant names:

• chr9-18504940-C-T
• rs769527362
• NM_001040272.6:c.175C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001040272.6(ADAMTSL1):​c.175C>T​(p.Arg59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R59G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADAMTSL1 NM_001040272.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

Genes affected

ADAMTSL1 (HGNC:14632): (ADAMTS like 1) This gene encodes a secreted protein and member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) family. This protein lacks the metalloproteinase and disintegrin-like domains, which are typical of the ADAMTS family, but contains other ADAMTS domains, including the thrombospondin type 1 motif. This protein may have important functions in the extracellular matrix. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040272.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL1	NM_001040272.6	MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 2 of 29	NP_001035362.3	Q8N6G6-3
	ADAMTSL1	NM_052866.5		c.175C>T	p.Arg59Cys	missense	Exon 2 of 13	NP_443098.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL1	ENST00000380548.9	TSL:5 MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 2 of 29	ENSP00000369921.4	Q8N6G6-3
	ADAMTSL1	ENST00000327883.11	TSL:1	c.175C>T	p.Arg59Cys	missense	Exon 2 of 13	ENSP00000327887.7	Q8N6G6-1
	ADAMTSL1	ENST00000380566.8	TSL:1	c.175C>T	p.Arg59Cys	missense	Exon 2 of 10	ENSP00000369940.4	Q8N6G6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457138 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725090

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 43990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111130

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.61		Loss of MoRF binding (P = 0.0052)
MVP		0.65
MPC		0.46
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.52
gMVP		0.55
Mutation Taster		=26/73	disease causing

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: rs769527362; hg19: chr9-18504938; COSMIC: COSV52812511;