1-150558574-G-C

Variant names:

• chr1-150558574-G-C
• rs10749657
• NM_019032.6:c.2484G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_019032.6(ADAMTSL4):​c.2484G>C​(p.Pro828Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P828P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTSL4 NM_019032.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.85
• Publications: 16 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.

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.2484G>C	p.Pro828Pro	synonymous	Exon 15 of 19	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.2553G>C	p.Pro851Pro	synonymous	Exon 16 of 20	NP_001275537.1
	ADAMTSL4	NM_001378596.1		c.2484G>C	p.Pro828Pro	synonymous	Exon 15 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.2484G>C	p.Pro828Pro	synonymous	Exon 15 of 19	ENSP00000271643.4
	ADAMTSL4	ENST00000369038.6	TSL:1	c.2484G>C	p.Pro828Pro	synonymous	Exon 13 of 17	ENSP00000358034.2
	ADAMTSL4	ENST00000369039.9	TSL:5	c.2553G>C	p.Pro851Pro	synonymous	Exon 16 of 20	ENSP00000358035.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461700 Hom.: 0 Cov.: 86 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.029
DANN	Benign	0.77
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

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: rs10749657; hg19: chr1-150531050;