9-18533272-T-C

Variant names:

• chr9-18533272-T-C
• NM_001040272.6:c.217T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040272.6(ADAMTSL1):​c.217T>C​(p.Tyr73His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTSL1 NM_001040272.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL1	NM_001040272.6	c.217T>C	p.Tyr73His	missense_variant	Exon 3 of 29	ENST00000380548.9	NP_001035362.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL1	ENST00000380548.9	c.217T>C	p.Tyr73His	missense_variant	Exon 3 of 29	5	NM_001040272.6	ENSP00000369921.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217T>C (p.Y73H) alteration is located in exon 3 (coding exon 3) of the ADAMTSL1 gene. This alteration results from a T to C substitution at nucleotide position 217, causing the tyrosine (Y) at amino acid position 73 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;L;.;.;L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	.;D;N;D;D;D;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	.;D;T;T;T;T;D
Sift4G	Uncertain	0.013	.;D;D;T;T;T;T
Polyphen		1.0	.;D;.;.;.;D;.
Vest4		0.70, 0.63, 0.68, 0.68, 0.68, 0.69
MutPred		0.46		.;Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);
MVP		0.40
MPC		0.45
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-18533270;