Genetic Variant ADAMTSL3:p.Thr5Ser (chr15-83655774-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_207517.3(ADAMTSL3):c.13A>T(p.Thr5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ADAMTSL3
NM_207517.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Publications

0 publications found

Variant links:

Genes affected

ADAMTSL3 (HGNC:14633): (ADAMTS like 3) Predicted to be involved in extracellular matrix organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ADAMTSL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018574268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL3	NM_207517.3 link	c.13A>T	p.Thr5Ser	missense_variant	Exon 2 of 30	ENST00000286744.10	NP_997400.2	P82987-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTSL3	ENST00000286744.10 link	c.13A>T	p.Thr5Ser	missense_variant	Exon 2 of 30	1	NM_207517.3	ENSP00000286744.5	P82987-1
ADAMTSL3	ENST00000567476.1 link	c.13A>T	p.Thr5Ser	missense_variant	Exon 2 of 30	1		ENSP00000456313.1	P82987-2
ADAMTSL3	ENST00000561483.5 link	n.228A>T		non_coding_transcript_exon_variant	Exon 2 of 27	5
ADAMTSL3	ENST00000569510.5 link	n.228A>T		non_coding_transcript_exon_variant	Exon 2 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251234

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.000493

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000144

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.13A>T (p.T5S) alteration is located in exon 2 (coding exon 1) of the ADAMTSL3 gene. This alteration results from a A to T substitution at nucleotide position 13, causing the threonine (T) at amino acid position 5 to be replaced by a serine (S). 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

Benign

0.090

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0049

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.28

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N

PhyloP100

1.3

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.030

N;N

REVEL

Benign

0.041

Sift

Benign

0.063

T;D

Sift4G

Benign

0.34

T;T

Polyphen

0.0090

B;B

Vest4

0.17

MVP

0.60

MPC

0.11

ClinPred

0.013

GERP RS

3.2

Varity_R

0.060

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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15-83655774-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over