Genetic Variant SIPA1:p.Glu42Gln (chr11-65641045-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006747.4(SIPA1):c.124G>C(p.Glu42Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,441,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E42K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SIPA1
NM_006747.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.01

Publications

0 publications found

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 was made for transcript

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=0.4110991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4 link	c.124G>C	p.Glu42Gln	missense_variant	Exon 2 of 16	ENST00000534313.6	NP_006738.3	Q96FS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1	ENST00000534313.6 link	c.124G>C	p.Glu42Gln	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1		Q96FS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000483

AC:

AN:

207144

AF XY:

0.00000870

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1441996

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

42360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25762

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39258

South Asian (SAS)

AF:

0.00

AC:

AN:

85280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106558

Other (OTH)

AF:

0.00

AC:

AN:

59820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Uncertain

-0.011

MutationAssessor

Uncertain

2.0

M;.;.;M

PhyloP100

7.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.94

N;D;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Benign

0.081

T;D;T;T

Polyphen

0.99

D;.;D;D

Vest4

0.16

MutPred

0.077

Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);

MVP

0.89

MPC

1.2

ClinPred

0.65

GERP RS

5.3

Varity_R

0.21

gMVP

0.40

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-65641045-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over