rs121912615

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 6P and 6B. PS3PP3PP5BP4BS1_SupportingBS2

The NM_001041.4(SI):c.1730T>G(p.Val577Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,605,538 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000441994: Functional studies performed by Alfalah et al. (2009) show that the p.Val577Gly variant results in a protein that is misfolded with a subsequent loss of enzyme activity. The variant protein was also shown to exist exclusively as a mannose-rich glycosylated species and to be retained in the endoplasmic reticulum." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V577D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

SI
NM_001041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:1O:1

Conservation

PhyloP100: 8.54

Publications

18 publications found

Variant links:

Genes affected

SI (HGNC:10856): (sucrase-isomaltase) This gene encodes a sucrase-isomaltase enzyme that is expressed in the intestinal brush border. The encoded protein is synthesized as a precursor protein that is cleaved by pancreatic proteases into two enzymatic subunits sucrase and isomaltase. These two subunits heterodimerize to form the sucrose-isomaltase complex. This complex is essential for the digestion of dietary carbohydrates including starch, sucrose and isomaltose. Mutations in this gene are the cause of congenital sucrase-isomaltase deficiency.[provided by RefSeq, Apr 2010]

SI Gene-Disease associations (from GenCC):

congenital sucrase-isomaltase deficiency
Inheritance: SD, AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

SI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000441994: Functional studies performed by Alfalah et al. (2009) show that the p.Val577Gly variant results in a protein that is misfolded with a subsequent loss of enzyme activity. The variant protein was also shown to exist exclusively as a mannose-rich glycosylated species and to be retained in the endoplasmic reticulum.; SCV000713110: "In vitro functional studies of the p.Val577Gly variant report an impact to protein folding (Alfalah 2009)."; SCV005418754: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000567692: Published functional studies demonstrate a damaging effect with misfolding of the SI protein, preventing the protein from exiting the endoplasmic reticulum and resulting in loss of enzymatic function (PMID: 19121318, 35985447);

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

PP5

Variant 3-165046998-A-C is Pathogenic according to our data. Variant chr3-165046998-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1418.

BP4

Computational evidence support a benign effect (MetaRNN=0.088983625). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00126 (192/152260) while in subpopulation NFE AF = 0.00212 (144/68010). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001041.4. 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
	SI	NM_001041.4	MANE Select	c.1730T>G	p.Val577Gly	missense	Exon 16 of 48	NP_001032.2	P14410

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SI	ENST00000264382.8	TSL:1 MANE Select	c.1730T>G	p.Val577Gly	missense	Exon 16 of 48	ENSP00000264382.3	P14410

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00160

AC:

392

AN:

244938

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000298

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00169

GnomAD4 exome

AF:

0.00248

AC:

3601

AN:

1453278

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1738

AN XY:

722932

show subpopulations

African (AFR)

AF:

0.000423

AC:

AN:

33126

American (AMR)

AF:

0.000296

AC:

AN:

43968

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.000839

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.000808

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00294

AC:

3252

AN:

1107440

Other (OTH)

AF:

0.00210

AC:

126

AN:

59986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

149

298

446

595

744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.00126

AC:

192

AN:

152260

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41572

American (AMR)

AF:

0.000589

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00212

AC:

144

AN:

68010

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00223

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sucrase-isomaltase deficiency (11)

not provided (6)

SI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.089

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

8.5

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.52

MVP

0.95

MPC

0.074

ClinPred

0.11

GERP RS

5.4

Varity_R

0.95

gMVP

0.69

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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