chr5-129461462-C-T

Position:

• chr5-129461462-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_133638.6(ADAMTS19):​c.452C>T​(p.Pro151Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,459,536 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: ADAMTS19 NM_133638.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.585

Genes affected

ADAMTS19 (HGNC:17111): (ADAM metallopeptidase with thrombospondin type 1 motif 19) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene has high sequence similarity to the protein encoded by ADAMTS16, another family member. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024986118).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000401 (61/152048) while in subpopulation AMR AF= 0.000981 (15/15288). AF 95% confidence interval is 0.000604. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS19	NM_133638.6	c.452C>T	p.Pro151Leu	missense_variant	2/23	ENST00000274487.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS19	ENST00000274487.9	c.452C>T	p.Pro151Leu	missense_variant	2/23	1	NM_133638.6	P1
ADAMTS19	ENST00000505791.5	c.91+980C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 151942 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000439 AC: 29 AN: 66106 Hom.: 0 AF XY: 0.000392 AC XY: 15 AN XY: 38284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000349

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000410 AC: 536 AN: 1307488 Hom.: 4 Cov.: 32 AF XY: 0.000407 AC XY: 262 AN XY: 643874

Gnomad4 AFR exome AF: 0.000651

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000347

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.000682

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152048 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74326

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000741 Hom.: 0

Bravo AF: 0.000385

ExAC AF: 0.000173 AC: 4

Asia WGS AF: 0.000292 AC: 1 AN: 3442

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.434C>T (p.P145L) alteration is located in exon 2 (coding exon 2) of the ADAMTS19 gene. This alteration results from a C to T substitution at nucleotide position 434, causing the proline (P) at amino acid position 145 to be replaced by a leucine (L). 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	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.94
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.58	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
REVEL	Benign	0.081
Polyphen		0.0	.;B
MutPred		0.36		.;Loss of glycosylation at P145 (P = 2e-04);
MVP		0.26
MPC		1.5
ClinPred		0.014	T
GERP RS		-3.1
Varity_R		0.054
gMVP		0.30

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

Other links and lift over

dbSNP: rs778870140; hg19: chr5-128797155;