rs76075180

Variant names:

• chr1-150553917-G-A
• rs76075180
• NM_019032.6:c.926G>A

Variant summary

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

The NM_019032.6(ADAMTSL4):​c.926G>A​(p.Arg309Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,611,512 control chromosomes in the GnomAD database, including 1,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R309G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (59 hom., cov: 30)
  • Exomes 𝑓: 0.010 (943 hom.)
• Consequence: ADAMTSL4 NM_019032.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.189
• Publications: 7 publications found

Genes affected

ADAMTSL4 (HGNC:19706): (ADAMTS like 4) This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Sep 2014]

ADAMTSL4-AS2 (HGNC:40895): (ADAMTSL4 antisense RNA 2)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001585871).
• BP6: Variant 1-150553917-G-A is Benign according to our data. Variant chr1-150553917-G-A is described in ClinVar as Benign. ClinVar VariationId is 292524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019032.6. 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
	ADAMTSL4	NM_019032.6	MANE Select	c.926G>A	p.Arg309Gln	missense	Exon 6 of 19	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.926G>A	p.Arg309Gln	missense	Exon 6 of 20	NP_001275537.1
	ADAMTSL4	NM_001378596.1		c.926G>A	p.Arg309Gln	missense	Exon 6 of 19	NP_001365525.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	ENST00000271643.9	TSL:5 MANE Select	c.926G>A	p.Arg309Gln	missense	Exon 6 of 19	ENSP00000271643.4
	ADAMTSL4	ENST00000369038.6	TSL:1	c.926G>A	p.Arg309Gln	missense	Exon 4 of 17	ENSP00000358034.2
	ADAMTSL4	ENST00000369039.9	TSL:5	c.926G>A	p.Arg309Gln	missense	Exon 6 of 20	ENSP00000358035.5

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1692 AN: 152156 Hom.: 57 Cov.: 30

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0690

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0592

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0314 AC: 7572 AN: 240808 AF XY: 0.0260

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.000614

Gnomad EAS exome AF: 0.0519

Gnomad FIN exome AF: 0.000661

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0100 AC: 14656 AN: 1459238 Hom.: 943 Cov.: 38 AF XY: 0.00981 AC XY: 7120 AN XY: 725870

African (AFR) AF: 0.00111 AC: 37 AN: 33434

American (AMR) AF: 0.155 AC: 6823 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.00108 AC: 28 AN: 26036

East Asian (EAS) AF: 0.0963 AC: 3818 AN: 39628

South Asian (SAS) AF: 0.0227 AC: 1953 AN: 86026

European-Finnish (FIN) AF: 0.000683 AC: 36 AN: 52738

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.00133 AC: 1477 AN: 1111214

Other (OTH) AF: 0.00786 AC: 474 AN: 60288

GnomAD4 genome AF: 0.0111 AC: 1689 AN: 152274 Hom.: 59 Cov.: 30 AF XY: 0.0129 AC XY: 961 AN XY: 74444

African (AFR) AF: 0.00190 AC: 79 AN: 41552

American (AMR) AF: 0.0689 AC: 1055 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0588 AC: 304 AN: 5170

South Asian (SAS) AF: 0.0294 AC: 142 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68008

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00514 Hom.: 47

Bravo AF: 0.0189

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0249 AC: 3011

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Ectopia lentis 2, isolated, autosomal recessive (2)
-	-	1	Ectopia lentis et pupillae (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.023
Sift	Benign	0.18	T
Sift4G	Benign	0.31	T
Polyphen		0.052	B
Vest4		0.053
MPC		0.14
ClinPred		0.0050	T
GERP RS		2.3
Varity_R		0.052
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76075180; hg19: chr1-150526393; COSMIC: COSV55000046; COSMIC: COSV55000046;