15-84037709-C-T

Variant names:

• chr15-84037709-C-T
• rs950169
• NM_207517.3:c.4979C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207517.3(ADAMTSL3):​c.4979C>T​(p.Thr1660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,601,146 control chromosomes in the GnomAD database, including 51,901 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3670 hom., cov: 33)
  • Exomes 𝑓: 0.25 (48231 hom.)
• Consequence: ADAMTSL3 NM_207517.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005163908).
• BP6: Variant 15-84037709-C-T is Benign according to our data. Variant chr15-84037709-C-T is described in ClinVar as [Benign]. Clinvar id is 1268691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL3	NM_207517.3	c.4979C>T	p.Thr1660Ile	missense_variant	Exon 30 of 30	ENST00000286744.10	NP_997400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL3	ENST00000286744.10	c.4979C>T	p.Thr1660Ile	missense_variant	Exon 30 of 30	1	NM_207517.3	ENSP00000286744.5
ADAMTSL3	ENST00000567476.1	c.4987-54C>T		intron_variant	Intron 29 of 29	1		ENSP00000456313.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29376 AN: 152098 Hom.: 3670 Cov.: 33

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.222 AC: 53411 AN: 240738 Hom.: 6762 AF XY: 0.230 AC XY: 29949 AN XY: 129938

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.0475

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.251 AC: 363272 AN: 1448930 Hom.: 48231 Cov.: 32 AF XY: 0.252 AC XY: 181539 AN XY: 720624

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.0440

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.193 AC: 29373 AN: 152216 Hom.: 3670 Cov.: 33 AF XY: 0.192 AC XY: 14316 AN XY: 74422

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.0526

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.209

Alfa AF: 0.259 Hom.: 13588

Bravo AF: 0.183

TwinsUK AF: 0.269 AC: 998

ALSPAC AF: 0.259 AC: 998

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.270 AC: 2323

ExAC AF: 0.221 AC: 26844

Asia WGS AF: 0.141 AC: 492 AN: 3478

EpiCase AF: 0.289

EpiControl AF: 0.288

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19197363, 21239144) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.055	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0	B
Vest4		0.028
MPC		0.13
ClinPred		0.023	T
GERP RS		-0.022
Varity_R		0.12
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs950169; hg19: chr15-84706461; COSMIC: COSV54442298;