Genetic Variant SIAE:p.Met89Val (chr11-124660768-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_170601.5(SIAE):c.265A>G(p.Met89Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,614,108 control chromosomes in the GnomAD database, including 2,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 159 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2177 hom. )

Consequence

SIAE
NM_170601.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.0520

Publications

24 publications found

Variant links:

Genes affected

SIAE (HGNC:18187): (sialic acid acetylesterase) This gene encodes an enzyme which removes 9-O-acetylation modifications from sialic acids. Mutations in this gene are associated with susceptibility to autoimmune disease 6. Multiple transcript variants encoding different isoforms, found either in the cytosol or in the lysosome, have been found for this gene.[provided by RefSeq, Feb 2011]

SIAE Gene-Disease associations (from GenCC):

autoimmune disease, susceptibility to, 6
Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

SIAE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025379956).

BP6

Variant 11-124660768-T-C is Benign according to our data. Variant chr11-124660768-T-C is described in ClinVar as Benign. ClinVar VariationId is 1352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170601.5. 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
	SIAE	NM_170601.5	MANE Select	c.265A>G	p.Met89Val	missense	Exon 3 of 10	NP_733746.1	Q9HAT2-1
	SIAE	NM_001199922.2		c.160A>G	p.Met54Val	missense	Exon 5 of 12	NP_001186851.1	Q9HAT2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIAE	ENST00000263593.8	TSL:1 MANE Select	c.265A>G	p.Met89Val	missense	Exon 3 of 10	ENSP00000263593.3	Q9HAT2-1
SIAE	ENST00000618733.4	TSL:1	c.160A>G	p.Met54Val	missense	Exon 5 of 12	ENSP00000478211.1	Q9HAT2-2
SIAE	ENST00000436137.2	TSL:1	n.378A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5648

AN:

152200

Hom.:

159

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00996

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.0614

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0578

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0377

AC:

9478

AN:

251410

AF XY:

0.0385

show subpopulations

Gnomad AFR exome

AF:

0.00929

Gnomad AMR exome

AF:

0.0149

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.0626

Gnomad NFE exome

AF:

0.0548

Gnomad OTH exome

AF:

0.0401

GnomAD4 exome

AF:

0.0511

AC:

74660

AN:

1461790

Hom.:

2177

Cov.:

AF XY:

0.0503

AC XY:

36601

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00690

AC:

231

AN:

33480

American (AMR)

AF:

0.0152

AC:

682

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0249

AC:

651

AN:

26132

East Asian (EAS)

AF:

0.00197

AC:

AN:

39694

South Asian (SAS)

AF:

0.0256

AC:

2206

AN:

86258

European-Finnish (FIN)

AF:

0.0651

AC:

3480

AN:

53416

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0580

AC:

64543

AN:

1111928

Other (OTH)

AF:

0.0447

AC:

2702

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3983

7966

11948

15931

19914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2332

4664

6996

9328

11660

<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:

0.0371

AC:

5648

AN:

152318

Hom.:

159

Cov.:

AF XY:

0.0372

AC XY:

2771

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00994

AC:

413

AN:

41570

American (AMR)

AF:

0.0250

AC:

382

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5192

South Asian (SAS)

AF:

0.0201

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0614

AC:

652

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0578

AC:

3934

AN:

68026

Other (OTH)

AF:

0.0302

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0465

Hom.:

440

Bravo

AF:

0.0328

TwinsUK

AF:

0.0642

AC:

238

ALSPAC

AF:

0.0646

AC:

249

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.0570

AC:

490

ExAC

AF:

0.0387

AC:

4698

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0513

EpiControl

AF:

0.0481

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autoimmune disease, susceptibility to, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.51

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.13

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.84

PhyloP100

-0.052

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

REVEL

Benign

0.18

Sift

Benign

0.43

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.095

MPC

0.14

ClinPred

0.0012

GERP RS

-0.45

Varity_R

0.034

gMVP

0.48

Mutation Taster

=96/4

polymorphism (auto)

(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