NM_207517.3:c.1981G>T

Variant names:

• chr15-83913372-G-T
• rs4842838
• NM_207517.3:c.1981G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207517.3(ADAMTSL3):​c.1981G>T​(p.Val661Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,611,870 control chromosomes in the GnomAD database, including 255,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31001 hom., cov: 31)
  • Exomes 𝑓: 0.55 (224802 hom.)
• Consequence: ADAMTSL3 NM_207517.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.250
• Publications: 79 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.850039E-7).
• BP6: Variant 15-83913372-G-T is Benign according to our data. Variant chr15-83913372-G-T is described in ClinVar as Benign. ClinVar VariationId is 1273050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207517.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL3	NM_207517.3	MANE Select	c.1981G>T	p.Val661Leu	missense	Exon 16 of 30	NP_997400.2
	ADAMTSL3	NM_001301110.2		c.1981G>T	p.Val661Leu	missense	Exon 16 of 30	NP_001288039.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL3	ENST00000286744.10	TSL:1 MANE Select	c.1981G>T	p.Val661Leu	missense	Exon 16 of 30	ENSP00000286744.5
	ADAMTSL3	ENST00000567476.1	TSL:1	c.1981G>T	p.Val661Leu	missense	Exon 16 of 30	ENSP00000456313.1
	ADAMTSL3	ENST00000561483.5	TSL:5	n.2196G>T		non_coding_transcript_exon	Exon 16 of 27

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95235 AN: 151922 Hom.: 30953 Cov.: 31

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.617

GnomAD2 exomes AF: 0.607 AC: 149827 AN: 246792 AF XY: 0.595

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.744

Gnomad FIN exome AF: 0.512

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.550 AC: 802953 AN: 1459830 Hom.: 224802 Cov.: 53 AF XY: 0.550 AC XY: 399327 AN XY: 726160

African (AFR) AF: 0.798 AC: 26713 AN: 33476

American (AMR) AF: 0.784 AC: 34994 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 15864 AN: 26124

East Asian (EAS) AF: 0.726 AC: 28796 AN: 39682

South Asian (SAS) AF: 0.609 AC: 52457 AN: 86200

European-Finnish (FIN) AF: 0.509 AC: 26532 AN: 52110

Middle Eastern (MID) AF: 0.659 AC: 3799 AN: 5766

European-Non Finnish (NFE) AF: 0.521 AC: 579292 AN: 1111454

Other (OTH) AF: 0.572 AC: 34506 AN: 60360

GnomAD4 genome AF: 0.627 AC: 95345 AN: 152040 Hom.: 31001 Cov.: 31 AF XY: 0.628 AC XY: 46703 AN XY: 74322

African (AFR) AF: 0.787 AC: 32648 AN: 41482

American (AMR) AF: 0.708 AC: 10815 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2141 AN: 3472

East Asian (EAS) AF: 0.744 AC: 3842 AN: 5166

South Asian (SAS) AF: 0.613 AC: 2947 AN: 4810

European-Finnish (FIN) AF: 0.512 AC: 5407 AN: 10552

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35521 AN: 67964

Other (OTH) AF: 0.616 AC: 1303 AN: 2116

Alfa AF: 0.558 Hom.: 117103

Bravo AF: 0.650

TwinsUK AF: 0.516 AC: 1914

ALSPAC AF: 0.539 AC: 2076

ESP6500AA AF: 0.776 AC: 3420

ESP6500EA AF: 0.537 AC: 4620

ExAC AF: 0.598 AC: 72562

Asia WGS AF: 0.673 AC: 2341 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.530

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.6
DANN	Benign	0.91
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.4	N
PhyloP100		0.25
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.76		Loss of glycosylation at T659 (P = 0.1653)
MPC		0.12
ClinPred		0.0028	T
GERP RS		-1.8
Varity_R		0.058
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4842838; hg19: chr15-84582124; COSMIC: COSV54438790;