rs150225445

Variant names:

• chr1-150559429-C-A
• rs150225445
• NM_019032.6:c.2906C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-150559429-C-A
• chr1-150559429-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019032.6(ADAMTSL4):​c.2906C>A​(p.Ala969Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,506 control chromosomes in the GnomAD database, including 202 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (9 hom., cov: 33)
  • Exomes 𝑓: 0.014 (193 hom.)
• Consequence: ADAMTSL4 NM_019032.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.433
• Publications: 5 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 Gene-Disease associations (from GenCC):

• ectopia lentis 2, isolated, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• ectopia lentis et pupillae

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057342947).
• BP6: Variant 1-150559429-C-A is Benign according to our data. Variant chr1-150559429-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00945 (1438/152240) while in subpopulation NFE AF = 0.0156 (1064/67994). AF 95% confidence interval is 0.0149. There are 9 homozygotes in GnomAd4. There are 710 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	NM_019032.6	MANE Select	c.2906C>A	p.Ala969Asp	missense	Exon 17 of 19	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.2975C>A	p.Ala992Asp	missense	Exon 18 of 20	NP_001275537.1	Q6UY14-3
	ADAMTSL4	NM_001378596.1		c.2906C>A	p.Ala969Asp	missense	Exon 17 of 19	NP_001365525.1	Q6UY14-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	ENST00000271643.9	TSL:5 MANE Select	c.2906C>A	p.Ala969Asp	missense	Exon 17 of 19	ENSP00000271643.4	Q6UY14-1
	ADAMTSL4	ENST00000369038.6	TSL:1	c.2906C>A	p.Ala969Asp	missense	Exon 15 of 17	ENSP00000358034.2	Q6UY14-1
	ADAMTSL4	ENST00000369039.9	TSL:5	c.2975C>A	p.Ala992Asp	missense	Exon 18 of 20	ENSP00000358035.5	Q6UY14-3

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1438 AN: 152122 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00938 AC: 2331 AN: 248514 AF XY: 0.00909

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.00271

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.0138 AC: 20102 AN: 1461266 Hom.: 193 Cov.: 33 AF XY: 0.0134 AC XY: 9717 AN XY: 726918

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.00349 AC: 156 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00116 AC: 100 AN: 86258

European-Finnish (FIN) AF: 0.0129 AC: 681 AN: 52814

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18431 AN: 1112000

Other (OTH) AF: 0.00990 AC: 598 AN: 60392

GnomAD4 genome AF: 0.00945 AC: 1438 AN: 152240 Hom.: 9 Cov.: 33 AF XY: 0.00954 AC XY: 710 AN XY: 74442

African (AFR) AF: 0.00243 AC: 101 AN: 41546

American (AMR) AF: 0.00654 AC: 100 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0156 AC: 1064 AN: 67994

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0109 Hom.: 20

Bravo AF: 0.00906

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.00926 AC: 1124

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign/Likely 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	L
PhyloP100		0.43
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.020
Sift	Benign	0.32	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.37
MPC		0.19
ClinPred		0.0049	T
GERP RS		-0.12
Varity_R		0.14
gMVP		0.25
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150225445; hg19: chr1-150531905; COSMIC: COSV106082832; COSMIC: COSV106082832;