Genetic Variant NM_020808.5:c.4445C>T (chr1-232425774-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020808.5(SIPA1L2):c.4445C>T(p.Ser1482Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00742 in 1,613,990 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 46 hom. )

Consequence

SIPA1L2
NM_020808.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.48

Publications

8 publications found

Variant links:

Genes affected

SIPA1L2 (HGNC:23800): (signal induced proliferation associated 1 like 2) This gene encodes a member of the signal-induced proliferation-associated 1 like family. Members of this family contain a GTPase activating domain, a PDZ domain and a C-terminal coiled-coil domain with a leucine zipper. A similar protein in rat acts as a GTPases for the small GTPase Rap. [provided by RefSeq, Sep 2015]

SIPA1L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009830773).

BP6

Variant 1-232425774-G-A is Benign according to our data. Variant chr1-232425774-G-A is described in ClinVar as Benign. ClinVar VariationId is 718930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020808.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1L2	NM_020808.5	MANE Select	c.4445C>T	p.Ser1482Leu	missense	Exon 18 of 23	NP_065859.3	Q9P2F8-1
	SIPA1L2	NM_001377488.1		c.4445C>T	p.Ser1482Leu	missense	Exon 18 of 22	NP_001364417.1	A0A6Q8PH54

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIPA1L2	ENST00000674635.1	MANE Select	c.4445C>T	p.Ser1482Leu	missense	Exon 18 of 23	ENSP00000502693.1	Q9P2F8-1
SIPA1L2	ENST00000676213.1		c.4598C>T	p.Ser1533Leu	missense	Exon 18 of 23	ENSP00000501897.1	A0A6Q8PFQ0
SIPA1L2	ENST00000964479.1		c.4598C>T	p.Ser1533Leu	missense	Exon 19 of 24	ENSP00000634538.1

Frequencies

GnomAD3 genomes

AF:

0.00493

AC:

750

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00833

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00557

AC:

1388

AN:

249064

AF XY:

0.00547

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00826

Gnomad NFE exome

AF:

0.00918

Gnomad OTH exome

AF:

0.00544

GnomAD4 exome

AF:

0.00768

AC:

11228

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00743

AC XY:

5401

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33478

American (AMR)

AF:

0.00163

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00130

AC:

AN:

26122

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86202

European-Finnish (FIN)

AF:

0.00914

AC:

488

AN:

53402

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00907

AC:

10087

AN:

1111914

Other (OTH)

AF:

0.00556

AC:

336

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

573

1145

1718

2290

2863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00492

AC:

750

AN:

152316

Hom.:

Cov.:

AF XY:

0.00483

AC XY:

360

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41570

American (AMR)

AF:

0.00183

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00833

AC:

567

AN:

68040

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00693

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00233

AC:

ESP6500EA

AF:

0.00824

AC:

ExAC

AF:

0.00618

AC:

749

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00830

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

0.031

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.012

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

PhyloP100

6.5

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.096

Sift

Uncertain

0.010

Sift4G

Benign

0.062

Polyphen

0.33

Vest4

0.65

MVP

0.093

MPC

0.20

ClinPred

0.028

GERP RS

4.8

Varity_R

0.19

gMVP

0.44

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over