Variant 11-65641070-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006747.4(SIPA1):c.149T>C(p.Leu50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,352 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIPA1
NM_006747.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

Variant links:

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]

SIPA1 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
SIPA1	NM_006747.4 linkuse as main transcript	c.149T>C	p.Leu50Pro	missense_variant	2/16	ENST00000534313.6	NP_006738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SIPA1	ENST00000534313.6 linkuse as main transcript	c.149T>C	p.Leu50Pro	missense_variant	2/16	1	NM_006747.4	ENSP00000436269	P1
SIPA1	ENST00000394224.3 linkuse as main transcript	c.149T>C	p.Leu50Pro	missense_variant	2/16	1		ENSP00000377771	P1
SIPA1	ENST00000527525.5 linkuse as main transcript	c.149T>C	p.Leu50Pro	missense_variant	2/17	2		ENSP00000433686
SIPA1	ENST00000533361.1 linkuse as main transcript	c.149T>C	p.Leu50Pro	missense_variant	3/3	4		ENSP00000436683

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447352

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.149T>C (p.L50P) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a T to C substitution at nucleotide position 149, causing the leucine (L) at amino acid position 50 to be replaced by a proline (P). 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

0.085

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.087

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.72

.;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.093

MutationAssessor

Benign

1.3

L;.;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.99

N;D;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.34

T;D;T;T

Polyphen

1.0

D;.;D;D

Vest4

0.15

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.86

MPC

2.0

ClinPred

0.88

GERP RS

5.4

Varity_R

0.35

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over