Variant 11-65641142-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006747.4(SIPA1):c.221G>A(p.Ser74Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,452,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

SIPA1
NM_006747.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31740028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1	NM_006747.4 linkuse as main transcript	c.221G>A	p.Ser74Asn	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.221G>A	p.Ser74Asn	missense_variant	2/16	1	NM_006747.4	ENSP00000436269	P1
SIPA1	ENST00000394224.3 linkuse as main transcript	c.221G>A	p.Ser74Asn	missense_variant	2/16	1		ENSP00000377771	P1
SIPA1	ENST00000527525.5 linkuse as main transcript	c.221G>A	p.Ser74Asn	missense_variant	2/17	2		ENSP00000433686
SIPA1	ENST00000533361.1 linkuse as main transcript	c.221G>A	p.Ser74Asn	missense_variant	3/3	4		ENSP00000436683

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000421

AC:

AN:

237494

Hom.:

AF XY:

0.00000765

AC XY:

AN XY:

130776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000523

AC:

AN:

1452250

Hom.:

Cov.:

AF XY:

0.0000484

AC XY:

AN XY:

722904

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:

0.0000684

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

May 18, 2022

The c.221G>A (p.S74N) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a G to A substitution at nucleotide position 221, causing the serine (S) at amino acid position 74 to be replaced by an asparagine (N). 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

Pathogenic

0.83

BayesDel_addAF

Benign

-0.0080

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.76

.;T;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

2.0

M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.2

N;D;N;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.30

T;D;T;T

Polyphen

0.99

D;.;D;D

Vest4

0.30

MutPred

0.16

Loss of phosphorylation at S74 (P = 0.0023);Loss of phosphorylation at S74 (P = 0.0023);Loss of phosphorylation at S74 (P = 0.0023);Loss of phosphorylation at S74 (P = 0.0023);

MVP

0.89

MPC

1.6

ClinPred

0.58

GERP RS

5.0

Varity_R

0.47

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over