11-65640958-C-G

Variant names:

• chr11-65640958-C-G
• NM_006747.4:c.37C>G

Variant summary

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

The NM_006747.4(SIPA1):​c.37C>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R13W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.336
• Publications: 0 publications found

Genes affected

SIPA1 (HGNC:10885): (signal-induced proliferation-associated 1) The product of this gene is a mitogen induced GTPase activating protein (GAP). It exhibits a specific GAP activity for Ras-related regulatory proteins Rap1 and Rap2, but not for Ran or other small GTPases. This protein may also hamper mitogen-induced cell cycle progression when abnormally or prematurely expressed. It is localized to the perinuclear region. Two alternatively spliced variants encoding the same isoform have been characterized to date. [provided by RefSeq, Jul 2008]

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=0.26624548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.37C>G	p.Arg13Gly	missense_variant	Exon 2 of 16	ENST00000534313.6	NP_006738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1	ENST00000534313.6	c.37C>G	p.Arg13Gly	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.37C>G (p.R13G) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a C to G substitution at nucleotide position 37, causing the arginine (R) at amino acid position 13 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;.;T;T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.0	M;.;.;M
PhyloP100		-0.34
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N;D;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.67	P;.;P;P
Vest4		0.23
MutPred		0.22		Loss of MoRF binding (P = 0.0225);Loss of MoRF binding (P = 0.0225);Loss of MoRF binding (P = 0.0225);Loss of MoRF binding (P = 0.0225);
MVP		0.85
MPC		1.0
ClinPred		0.64	D
GERP RS		1.8
Varity_R		0.27
gMVP		0.51
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

hg19: chr11-65408429;