chr19-38081727-G-GGCCACC

Variant names:

• chr19-38081727-G-GGCCACC
• rs562186095
• NM_015073.3:c.187_192dupGCCACC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015073.3(SIPA1L3):​c.187_192dupGCCACC​(p.Ala63_Thr64dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,602,804 control chromosomes in the GnomAD database, including 118 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (96 hom.)
• Consequence: SIPA1L3 NM_015073.3 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-38081727-G-GGCCACC is Benign according to our data. Variant chr19-38081727-G-GGCCACC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 782055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

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_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	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_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	Exon 3 of 22	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.187_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	Exon 2 of 21	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.187_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	Exon 3 of 22	ENSP00000581559.1

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1199 AN: 152072 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0650

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00937 AC: 2063 AN: 220134 AF XY: 0.00843

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00614 AC: 8909 AN: 1450614 Hom.: 96 Cov.: 30 AF XY: 0.00600 AC XY: 4330 AN XY: 721318

African (AFR) AF: 0.00189 AC: 63 AN: 33312

American (AMR) AF: 0.0150 AC: 655 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 703 AN: 25858

East Asian (EAS) AF: 0.0440 AC: 1714 AN: 38978

South Asian (SAS) AF: 0.00408 AC: 350 AN: 85696

European-Finnish (FIN) AF: 0.00282 AC: 139 AN: 49276

Middle Eastern (MID) AF: 0.0262 AC: 148 AN: 5640

European-Non Finnish (NFE) AF: 0.00406 AC: 4503 AN: 1108352

Other (OTH) AF: 0.0106 AC: 634 AN: 59878

GnomAD4 genome AF: 0.00784 AC: 1193 AN: 152190 Hom.: 22 Cov.: 33 AF XY: 0.00808 AC XY: 601 AN XY: 74418

African (AFR) AF: 0.00173 AC: 72 AN: 41548

American (AMR) AF: 0.0160 AC: 244 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3466

East Asian (EAS) AF: 0.0646 AC: 333 AN: 5154

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00500 AC: 340 AN: 67976

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00587 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=82/18	polymorphism (auto)

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: COSV55910526; COSMIC: COSV55910526;