chr19-1506822-C-A

Variant names:

• chr19-1506822-C-A
• rs200191805
• NM_213604.3:c.959G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213604.3(ADAMTSL5):​c.959G>T​(p.Arg320Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,541,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: ADAMTSL5 NM_213604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09547448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL5	NM_213604.3	c.959G>T	p.Arg320Met	missense_variant	Exon 10 of 12	ENST00000330475.9	NP_998769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL5	ENST00000330475.9	c.959G>T	p.Arg320Met	missense_variant	Exon 10 of 12	2	NM_213604.3	ENSP00000327608.3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152026 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000422 AC: 60 AN: 142034 Hom.: 0 AF XY: 0.000381 AC XY: 29 AN XY: 76198

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.0000958

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000641

Gnomad OTH exome AF: 0.000251

GnomAD4 exome AF: 0.000557 AC: 774 AN: 1388994 Hom.: 1 Cov.: 36 AF XY: 0.000568 AC XY: 389 AN XY: 685318

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.0000625

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000536

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000609

Gnomad4 OTH exome AF: 0.000591

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.000314

ExAC AF: 0.000247 AC: 22

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.959G>T (p.R320M) alteration is located in exon 10 (coding exon 9) of the ADAMTSL5 gene. This alteration results from a G to T substitution at nucleotide position 959, causing the arginine (R) at amino acid position 320 to be replaced by a methionine (M). 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	-0.24	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.51	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0050	D;D;.
Vest4		0.50
MVP		0.79
MPC		0.16
ClinPred		0.085	T
GERP RS		3.0
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs200191805; hg19: chr19-1506821;