rs734204

Variant names:

• chr19-38049348-A-G
• rs734204
• NM_015073.3:c.-311+20192A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015073.3(SIPA1L3):​c.-311+20192A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,010 control chromosomes in the GnomAD database, including 14,048 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (14048 hom., cov: 32)
• Consequence: SIPA1L3 NM_015073.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 6 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):

• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cataract 45

  Inheritance: Unknown, SD, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L3	NM_015073.3	c.-311+20192A>G		intron_variant	Intron 2 of 21	ENST00000222345.11	NP_055888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1L3	ENST00000222345.11	c.-311+20192A>G		intron_variant	Intron 2 of 21	1	NM_015073.3	ENSP00000222345.4
SIPA1L3	ENST00000476317.2	n.415+20192A>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61371 AN: 151892 Hom.: 14021 Cov.: 32

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.387

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

GnomAD4 genome AF: 0.404 AC: 61463 AN: 152010 Hom.: 14048 Cov.: 32 AF XY: 0.403 AC XY: 29945 AN XY: 74296

African (AFR) AF: 0.627 AC: 25995 AN: 41458

American (AMR) AF: 0.330 AC: 5035 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 993 AN: 3468

East Asian (EAS) AF: 0.128 AC: 663 AN: 5160

South Asian (SAS) AF: 0.383 AC: 1848 AN: 4820

European-Finnish (FIN) AF: 0.335 AC: 3538 AN: 10564

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22181 AN: 67964

Other (OTH) AF: 0.385 AC: 813 AN: 2110

Alfa AF: 0.350 Hom.: 31826

Bravo AF: 0.412

Asia WGS AF: 0.341 AC: 1185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.37
DANN	Benign	0.64
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs734204; hg19: chr19-38539988; COSMIC: COSV55910794;