19-38081727-GGCCACCGCCACCGCCACC-GGCCACCGCCACC

Variant names:

• chr19-38081727-GGCCACC-G
• rs562186095
• NM_015073.3:c.187_192delGCCACC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_015073.3(SIPA1L3):​c.187_192delGCCACC​(p.Ala63_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 0.00112 in 1,602,790 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: SIPA1L3 NM_015073.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 19-38081727-GGCCACC-G is Benign according to our data. Variant chr19-38081727-GGCCACC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2054669.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,SD,Unknown gene

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.187_192delGCCACC	p.Ala63_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.187_192delGCCACC	p.Ala63_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.187_192delGCCACC	p.Ala63_Thr64del	conservative_inframe_deletion	Exon 2 of 21	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.187_192delGCCACC	p.Ala63_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000581559.1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00115 AC: 254 AN: 220134 AF XY: 0.00100

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00202

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000551

GnomAD4 exome AF: 0.00102 AC: 1480 AN: 1450600 Hom.: 2 AF XY: 0.000934 AC XY: 674 AN XY: 721312

African (AFR) AF: 0.00501 AC: 167 AN: 33312

American (AMR) AF: 0.00144 AC: 63 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25858

East Asian (EAS) AF: 0.00113 AC: 44 AN: 38976

South Asian (SAS) AF: 0.000583 AC: 50 AN: 85696

European-Finnish (FIN) AF: 0.00195 AC: 96 AN: 49266

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5642

European-Non Finnish (NFE) AF: 0.000870 AC: 964 AN: 1108348

Other (OTH) AF: 0.00139 AC: 83 AN: 59878

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74418

African (AFR) AF: 0.00443 AC: 184 AN: 41548

American (AMR) AF: 0.00131 AC: 20 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5154

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000633 AC: 43 AN: 67976

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000183 Hom.: 2

Bravo AF: 0.00212

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=183/17	polymorphism

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; COSMIC: COSV55917636; COSMIC: COSV55917636;