19-38080969-CAAA-CAAAA

Variant names:

• chr19-38080969-C-CA
• rs34741674
• NM_015073.3:c.-310-272dupA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015073.3(SIPA1L3):​c.-310-272dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0084 (4 hom., cov: 0)
• Consequence: SIPA1L3 NM_015073.3 intron
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 4 AD,Unknown,SD,AR 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.-310-272dupA		intron	N/A	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.-310-287_-310-286insA		intron	N/A	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.-310-287_-310-286insA		intron	N/A	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.-310-287_-310-286insA		intron	N/A	ENSP00000581559.1

Frequencies

GnomAD3 genomes AF: 0.00836 AC: 982 AN: 117450 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.00810

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.00224

Gnomad SAS AF: 0.00330

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.0654

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.0104

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00836 AC: 982 AN: 117494 Hom.: 4 Cov.: 0 AF XY: 0.00845 AC XY: 476 AN XY: 56334

African (AFR) AF: 0.00980 AC: 313 AN: 31930

American (AMR) AF: 0.00809 AC: 97 AN: 11986

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 80 AN: 2764

East Asian (EAS) AF: 0.00224 AC: 10 AN: 4460

South Asian (SAS) AF: 0.00332 AC: 12 AN: 3618

European-Finnish (FIN) AF: 0.00359 AC: 23 AN: 6412

Middle Eastern (MID) AF: 0.0561 AC: 11 AN: 196

European-Non Finnish (NFE) AF: 0.00776 AC: 418 AN: 53896

Other (OTH) AF: 0.0103 AC: 16 AN: 1550

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34741674; hg19: chr19-38571609;