19-38080969-CAAA-CAAAAAA

Variant names:

• chr19-38080969-C-CAAA
• rs34741674
• NM_015073.3:c.-310-274_-310-272dupAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_015073.3(SIPA1L3):​c.-310-274_-310-272dupAAA 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 0.00078 (3 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000782 (92/117576) while in subpopulation EAS AF = 0.0186 (83/4462). AF 95% confidence interval is 0.0154. There are 3 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.-310-274_-310-272dupAAA		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_-310-286insAAA		intron	N/A	ENSP00000222345.4	O60292
	SIPA1L3	ENST00000911499.1		c.-310-287_-310-286insAAA		intron	N/A	ENSP00000581558.1
	SIPA1L3	ENST00000911500.1		c.-310-287_-310-286insAAA		intron	N/A	ENSP00000581559.1

Frequencies

GnomAD3 genomes AF: 0.000757 AC: 89 AN: 117532 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000835

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.000825

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000185

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000782 AC: 92 AN: 117576 Hom.: 3 Cov.: 0 AF XY: 0.000922 AC XY: 52 AN XY: 56380

African (AFR) AF: 0.0000313 AC: 1 AN: 31932

American (AMR) AF: 0.0000834 AC: 1 AN: 11990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2768

East Asian (EAS) AF: 0.0186 AC: 83 AN: 4462

South Asian (SAS) AF: 0.00110 AC: 4 AN: 3622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.0000185 AC: 1 AN: 53942

Other (OTH) AF: 0.00129 AC: 2 AN: 1552

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
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34741674; hg19: chr19-38571609;