1-232425622-C-A

Variant names:

• chr1-232425622-C-A
• rs376047587
• NM_020808.5:c.4597G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020808.5(SIPA1L2):​c.4597G>T​(p.Ala1533Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000218 in 1,607,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SIPA1L2 NM_020808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.068883836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L2	NM_020808.5	c.4597G>T	p.Ala1533Ser	missense_variant	Exon 18 of 23	ENST00000674635.1	NP_065859.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1L2	ENST00000674635.1	c.4597G>T	p.Ala1533Ser	missense_variant	Exon 18 of 23		NM_020808.5	ENSP00000502693.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000334 AC: 8 AN: 239622 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1455372 Hom.: 0 Cov.: 31 AF XY: 0.0000263 AC XY: 19 AN XY: 723232

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39598

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4732

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109378

Other (OTH) AF: 0.000133 AC: 8 AN: 60050

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4597G>T (p.A1533S) alteration is located in exon 16 (coding exon 16) of the SIPA1L2 gene. This alteration results from a G to T substitution at nucleotide position 4597, causing the alanine (A) at amino acid position 1533 to be replaced by a serine (S). 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	0.064
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.39	.;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;.
PhyloP100		5.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.13	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.071	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.28
MutPred		0.18		Gain of glycosylation at A1533 (P = 0.0073);Gain of glycosylation at A1533 (P = 0.0073);.;
MVP		0.068
MPC		0.16
ClinPred		0.080	T
GERP RS		4.3
Varity_R		0.039
gMVP		0.14
Mutation Taster		=91/9	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: rs376047587; hg19: chr1-232561368;