19-38081641-C-T

Position:

• chr19-38081641-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015073.3(SIPA1L3):​c.76C>T​(p.Leu26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,455,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SIPA1L3 NM_015073.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14737552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIPA1L3	NM_015073.3	c.76C>T	p.Leu26Phe	missense_variant	3/22	ENST00000222345.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIPA1L3	ENST00000222345.11	c.76C>T	p.Leu26Phe	missense_variant	3/22	1	NM_015073.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000285 AC: 7 AN: 245336 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1455498 Hom.: 0 Cov.: 30 AF XY: 0.0000194 AC XY: 14 AN XY: 722846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000413 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This variant is present in population databases (rs746139052, gnomAD 0.005%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1385780). This variant has not been reported in the literature in individuals affected with SIPA1L3-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 26 of the SIPA1L3 protein (p.Leu26Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	0.52	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.19
Sift	Benign	0.063	T
Sift4G	Benign	0.15	T
Polyphen		0.11	B
Vest4		0.35
MutPred		0.18		Gain of methylation at R21 (P = 0.2124);
MVP		0.29
MPC		1.1
ClinPred		0.065	T
GERP RS		4.5
Varity_R		0.085
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs746139052; hg19: chr19-38572281;