rs562186095

Variant names:

• chr19-38081727-GGCCACCGCCACCGCCACC-G
• rs562186095
• NM_015073.3:c.175_192delGCCACCGCCACCGCCACC

Your query was ambiguous. Multiple possible variants found:

• chr19-38081727-GGCCACCGCCACCGCCACC-G
• chr19-38081727-GGCCACCGCCACCGCCACC-GGCCACC
• chr19-38081727-GGCCACCGCCACCGCCACC-GGCCACCGCCACC
• chr19-38081727-GGCCACCGCCACCGCCACC-GGCCACCGCCACCGCCACCGCCACC
• chr19-38081727-GGCCACCGCCACCGCCACC-GGCCACCGCCACCGCCACCGCCACCGCCACC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015073.3(SIPA1L3):​c.175_192delGCCACCGCCACCGCCACC​(p.Ala59_Thr64del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,450,622 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SIPA1L3 NM_015073.3 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

Genes affected

SIPA1L3 (HGNC:23801): (signal induced proliferation associated 1 like 3) This gene belongs to the signal induced proliferation associated 1 family of genes, which encode GTPase-activating proteins specific for the GTP-binding protein Rap1. Rap1 has been implicated in regulation of cell adhesion, cell polarity, and organization of the cytoskeleton. Like other members of the family, the protein encoded by this gene contains RapGAP and PDZ domains. In addition, this protein contains a C-terminal leucine zipper domain. This gene is proposed to function in epithelial cell morphogenesis and establishment or maintenance of polarity. Consistently, expression of the protein in cell culture showed localization to cell-cell borders in apical regions, and downregulation of the gene in 3D Caco2 cell culture resulted in abnormal cell polarity and morphogenesis. Allelic variants of this gene have been associated with congenital cataracts in humans. [provided by RefSeq, Feb 2016]

SIPA1L3 Gene-Disease associations (from GenCC):

• cataract 45

  Inheritance: AD, AR, SD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015073.3. 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
	SIPA1L3	NM_015073.3	MANE Select	c.175_192delGCCACCGCCACCGCCACC	p.Ala59_Thr64del	conservative_inframe_deletion	Exon 3 of 22	NP_055888.1	O60292

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1L3	ENST00000222345.11	TSL:1 MANE Select	c.175_192delGCCACCGCCACCGCCACC	p.Ala59_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.175_192delGCCACCGCCACCGCCACC	p.Ala59_Thr64del	conservative_inframe_deletion	Exon 2 of 21	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.175_192delGCCACCGCCACCGCCACC	p.Ala59_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000581559.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1450622 Hom.: 0 AF XY: 0.00000555 AC XY: 4 AN XY: 721320

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 38978

South Asian (SAS) AF: 0.00 AC: 0 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108358

Other (OTH) AF: 0.00 AC: 0 AN: 59878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000451526), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs562186095; hg19: chr19-38572367;