11-65641259-C-A

Variant names:

• chr11-65641259-C-A
• NM_006747.4:c.338C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006747.4(SIPA1):​c.338C>A​(p.Pro113His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 6.59

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.338C>A	p.Pro113His	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.338C>A	p.Pro113His	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1
SIPA1	ENST00000394224.3	c.338C>A	p.Pro113His	missense_variant	Exon 2 of 16	1		ENSP00000377771.3
SIPA1	ENST00000527525.5	c.338C>A	p.Pro113His	missense_variant	Exon 2 of 17	2		ENSP00000433686.1
SIPA1	ENST00000533361.1	c.*30C>A		downstream_gene_variant		4		ENSP00000436683.1

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

Dec 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338C>A (p.P113H) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a C to A substitution at nucleotide position 338, causing the proline (P) at amino acid position 113 to be replaced by a histidine (H). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.61
MutPred		0.33		Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);
MVP		0.90
MPC		1.7
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-65408730;