19-38081906-C-A

Position:

• chr19-38081906-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015073.3(SIPA1L3):​c.341C>A​(p.Ala114Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,614,148 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (104 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (87 hom.)
• Consequence: SIPA1L3 NM_015073.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.236

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023534298).
• BP6: Variant 19-38081906-C-A is Benign according to our data. Variant chr19-38081906-C-A is described in ClinVar as [Benign]. Clinvar id is 781448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1L3	NM_015073.3	c.341C>A	p.Ala114Asp	missense_variant	3/22	ENST00000222345.11	NP_055888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIPA1L3	ENST00000222345.11	c.341C>A	p.Ala114Asp	missense_variant	3/22	1	NM_015073.3	ENSP00000222345	P1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2961 AN: 152216 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00487 AC: 1224 AN: 251272 Hom.: 35 AF XY: 0.00351 AC XY: 477 AN XY: 135828

Gnomad AFR exome AF: 0.0674

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00195 AC: 2853 AN: 1461814 Hom.: 87 Cov.: 33 AF XY: 0.00166 AC XY: 1205 AN XY: 727208

Gnomad4 AFR exome AF: 0.0693

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.0195 AC: 2970 AN: 152334 Hom.: 104 Cov.: 33 AF XY: 0.0186 AC XY: 1389 AN XY: 74494

Gnomad4 AFR AF: 0.0678

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00436 Hom.: 32

Bravo AF: 0.0213

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00629 AC: 764

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.40	T
Polyphen		0.037	B
Vest4		0.31
MVP		0.093
MPC		0.69
ClinPred		0.0016	T
GERP RS		4.0
Varity_R		0.082
gMVP		0.41

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: rs73630827; hg19: chr19-38572546;