chr9-18622244-T-C

Variant names:

• chr9-18622244-T-C
• rs758055717
• NM_001040272.6:c.476T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040272.6(ADAMTSL1):​c.476T>C​(p.Ile159Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000161 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ADAMTSL1 NM_001040272.6 missense, splice_region
• Scores: Splicing: ADA: 0.03230
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.381113).

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.476T>C	p.Ile159Thr	missense splice_region	Exon 5 of 29	NP_001035362.3	Q8N6G6-3
	ADAMTSL1	NM_052866.5		c.476T>C	p.Ile159Thr	missense splice_region	Exon 5 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.476T>C	p.Ile159Thr	missense splice_region	Exon 5 of 29	ENSP00000369921.4	Q8N6G6-3
	ADAMTSL1	ENST00000327883.11	TSL:1	c.476T>C	p.Ile159Thr	missense splice_region	Exon 5 of 13	ENSP00000327887.7	Q8N6G6-1
	ADAMTSL1	ENST00000380566.8	TSL:1	c.476T>C	p.Ile159Thr	missense splice_region	Exon 5 of 10	ENSP00000369940.4	Q8N6G6-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250334 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461476 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111778

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.10	N
PhyloP100		3.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.17
Sift	Benign	0.36	T
Sift4G	Benign	0.32	T
Polyphen		0.98	D
Vest4		0.81
MutPred		0.54		Gain of disorder (P = 0.0585)
MVP		0.64
MPC		0.39
ClinPred		0.46	T
GERP RS		5.6
Varity_R		0.081
gMVP		0.47
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.032
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.010		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: rs758055717; hg19: chr9-18622242;