dbSNP rs781439867: SIPA1:p.Leu23Phe (chr11-65640988-C-T) – 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.67C>T(p.Leu23Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,434,076 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: 0.0000021 ( 0 hom. )

Consequence

SIPA1
NM_006747.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

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=0.3866104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4 link	c.67C>T	p.Leu23Phe	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.67C>T	p.Leu23Phe	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1		Q96FS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000503

AC:

AN:

198990

AF XY:

0.00000906

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:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1434076

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

712598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

41572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25144

East Asian (EAS)

AF:

0.00

AC:

AN:

39166

South Asian (SAS)

AF:

0.00

AC:

AN:

83538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1104560

Other (OTH)

AF:

0.00

AC:

AN:

59544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000853

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.67C>T (p.L23F) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a C to T substitution at nucleotide position 67, causing the leucine (L) at amino acid position 23 to be replaced by a phenylalanine (F). 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

0.34

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.65

.;T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.1

M;.;.;M

PhyloP100

2.5

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.7

N;D;N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Benign

0.090

T;D;T;T

Polyphen

0.97

D;.;D;D

Vest4

0.21

MutPred

0.24

Gain of methylation at K27 (P = 0.0824);Gain of methylation at K27 (P = 0.0824);Gain of methylation at K27 (P = 0.0824);Gain of methylation at K27 (P = 0.0824);

MVP

0.93

MPC

1.1

ClinPred

0.65

GERP RS

5.1

Varity_R

0.14

gMVP

0.34

Mutation Taster

=77/23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over