1-232402397-G-A

Variant names:

• chr1-232402397-G-A
• rs1302135006
• NM_020808.5:c.5017C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020808.5(SIPA1L2):​c.5017C>T​(p.Arg1673Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1673Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SIPA1L2 NM_020808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 9 publications found

Genes affected

SIPA1L2 (HGNC:23800): (signal induced proliferation associated 1 like 2) This gene encodes a member of the signal-induced proliferation-associated 1 like family. Members of this family contain a GTPase activating domain, a PDZ domain and a C-terminal coiled-coil domain with a leucine zipper. A similar protein in rat acts as a GTPases for the small GTPase Rap. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40243384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L2	NM_020808.5	c.5017C>T	p.Arg1673Trp	missense_variant	Exon 22 of 23	ENST00000674635.1	NP_065859.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1L2	ENST00000674635.1	c.5017C>T	p.Arg1673Trp	missense_variant	Exon 22 of 23		NM_020808.5	ENSP00000502693.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249158 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460826 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726682

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111290

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5017C>T (p.R1673W) alteration is located in exon 20 (coding exon 20) of the SIPA1L2 gene. This alteration results from a C to T substitution at nucleotide position 5017, causing the arginine (R) at amino acid position 1673 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.6	L;L;.
PhyloP100		4.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.58
MutPred		0.26		Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);.;
MVP		0.18
MPC		0.51
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.15
gMVP		0.31
Mutation Taster		=85/15	polymorphism

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: rs1302135006; hg19: chr1-232538143; COSMIC: COSV53387000; COSMIC: COSV53387000;