rs372530672

Variant names:

• chr1-232425604-T-G
• rs372530672
• NM_020808.5:c.4615A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020808.5(SIPA1L2):​c.4615A>C​(p.Met1539Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,593,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SIPA1L2 NM_020808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.315
• Publications: 1 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018495977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L2	NM_020808.5	c.4615A>C	p.Met1539Leu	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.4615A>C	p.Met1539Leu	missense_variant	Exon 18 of 23		NM_020808.5	ENSP00000502693.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000308 AC: 7 AN: 226950 AF XY: 0.0000244

Gnomad AFR exome AF: 0.000221

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000235

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 29 AN: 1440876 Hom.: 0 Cov.: 31 AF XY: 0.0000238 AC XY: 17 AN XY: 713680

African (AFR) AF: 0.000151 AC: 5 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 43008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.000612 AC: 24 AN: 39236

South Asian (SAS) AF: 0.00 AC: 0 AN: 84138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099782

Other (OTH) AF: 0.00 AC: 0 AN: 59336

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74366

African (AFR) AF: 0.000362 AC: 15 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000660 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4615A>C (p.M1539L) alteration is located in exon 16 (coding exon 16) of the SIPA1L2 gene. This alteration results from a A to C substitution at nucleotide position 4615, causing the methionine (M) at amino acid position 1539 to be replaced by a leucine (L). 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	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.0090	T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.59	.;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N;N;.
PhyloP100		0.32
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.29
MutPred		0.15		Gain of glycosylation at S1538 (P = 0.0686);Gain of glycosylation at S1538 (P = 0.0686);.;
MVP		0.068
MPC		0.16
ClinPred		0.012	T
GERP RS		-3.4
Varity_R		0.067
gMVP		0.13
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372530672; hg19: chr1-232561350;