Genetic Variant NM_213604.3:c.1123G>T (chr19-1506308-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_213604.3(ADAMTSL5):c.1123G>T(p.Ala375Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000287 in 1,394,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ADAMTSL5
NM_213604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

Variant links:

Genes affected

ADAMTSL5 (HGNC:27912): (ADAMTS like 5) Enables heparin binding activity and microfibril binding activity. Located in extracellular region and microfibril. [provided by Alliance of Genome Resources, Apr 2022]

ADAMTSL5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26704925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL5	NM_213604.3 link	c.1123G>T	p.Ala375Ser	missense_variant	Exon 12 of 12	ENST00000330475.9	NP_998769.2	Q6ZMM2Q0VD77X6R4H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTSL5	ENST00000330475.9 link	c.1123G>T	p.Ala375Ser	missense_variant	Exon 12 of 12	2	NM_213604.3	ENSP00000327608.3	X6R4H8
ADAMTSL5	ENST00000585700.5 link	n.1121G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 11	1
ADAMTSL5	ENST00000590440.5 link	n.1161G>T		non_coding_transcript_exon_variant	Exon 12 of 12	1
ADAMTSL5	ENST00000395467.6 link	c.350G>T	p.Gly117Val	missense_variant, splice_region_variant	Exon 11 of 11	5		ENSP00000378850.2	Q0VD77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000102

AC:

AN:

196814

Hom.:

AF XY:

0.00000957

AC XY:

AN XY:

104462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000717

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000287

AC:

AN:

1394752

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

685230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000106

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1123G>T (p.A375S) alteration is located in exon 12 (coding exon 11) of the ADAMTSL5 gene. This alteration results from a G to T substitution at nucleotide position 1123, causing the alanine (A) at amino acid position 375 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

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.075

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

M_CAP

Benign

0.084

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.58

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.75

REVEL

Benign

0.083

Sift

Benign

0.052

Sift4G

Uncertain

0.019

Vest4

0.33

MVP

0.37

MPC

0.48

ClinPred

0.88

GERP RS

3.4

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over