19-38081727-GGCCACCGCCACCGCCACC-GGCCACC

Variant names:

• chr19-38081727-GGCCACCGCCACC-G
• rs562186095
• NM_015073.3:c.181_192delGCCACCGCCACC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_015073.3(SIPA1L3):​c.181_192delGCCACCGCCACC​(p.Ala61_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 0.000336 in 1,602,810 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SIPA1L3 NM_015073.3 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter 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 -2 ACMG points.

• BP6: Variant 19-38081727-GGCCACCGCCACC-G is Benign according to our data. Variant chr19-38081727-GGCCACCGCCACC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1659558.Status of the report is criteria_provided_single_submitter, 1 stars.

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.181_192delGCCACCGCCACC	p.Ala61_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.181_192delGCCACCGCCACC	p.Ala61_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.181_192delGCCACCGCCACC	p.Ala61_Thr64del	conservative_inframe_deletion	Exon 2 of 21	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.181_192delGCCACCGCCACC	p.Ala61_Thr64del	conservative_inframe_deletion	Exon 3 of 22	ENSP00000581559.1

Frequencies

GnomAD3 genomes AF: 0.000993 AC: 151 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000286 AC: 63 AN: 220134 AF XY: 0.000295

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.000246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000189

Gnomad FIN exome AF: 0.000168

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000267 AC: 387 AN: 1450620 Hom.: 0 AF XY: 0.000273 AC XY: 197 AN XY: 721318

African (AFR) AF: 0.00297 AC: 99 AN: 33312

American (AMR) AF: 0.000275 AC: 12 AN: 43624

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

East Asian (EAS) AF: 0.000231 AC: 9 AN: 38976

South Asian (SAS) AF: 0.000257 AC: 22 AN: 85696

European-Finnish (FIN) AF: 0.0000406 AC: 2 AN: 49276

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5642

European-Non Finnish (NFE) AF: 0.000202 AC: 224 AN: 1108358

Other (OTH) AF: 0.000301 AC: 18 AN: 59878

GnomAD4 genome AF: 0.000999 AC: 152 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000847 AC XY: 63 AN XY: 74418

African (AFR) AF: 0.00301 AC: 125 AN: 41548

American (AMR) AF: 0.000262 AC: 4 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67976

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000367 Hom.: 2

Bravo AF: 0.00134

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=164/36	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;