chr3-165023746-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001041.4(SI):c.2923T>C(p.Tyr975His) variant causes a missense change. The variant allele was found at a frequency of 0.00496 in 1,610,422 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0048 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 20 hom. )

Consequence

SI
NM_001041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.70

Publications

15 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: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025785983).

BP6

Variant 3-165023746-A-G is Benign according to our data. Variant chr3-165023746-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344034.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00482 (730/151534) while in subpopulation AMR AF = 0.0118 (178/15120). AF 95% confidence interval is 0.0104. There are 8 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SI	NM_001041.4	MANE Select	c.2923T>C	p.Tyr975His	missense	Exon 26 of 48	NP_001032.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SI	ENST00000264382.8	TSL:1 MANE Select	c.2923T>C	p.Tyr975His	missense	Exon 26 of 48	ENSP00000264382.3

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

729

AN:

151416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00579

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.00817

GnomAD2 exomes

AF:

0.00420

AC:

1049

AN:

249710

AF XY:

0.00434

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.00558

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.00937

GnomAD4 exome

AF:

0.00497

AC:

7253

AN:

1458888

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

3666

AN XY:

725754

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33314

American (AMR)

AF:

0.00618

AC:

275

AN:

44514

Ashkenazi Jewish (ASJ)

AF:

0.00550

AC:

143

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86218

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00555

AC:

6163

AN:

1109994

Other (OTH)

AF:

0.00545

AC:

328

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

344

688

1033

1377

1721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.00482

AC:

730

AN:

151534

Hom.:

Cov.:

AF XY:

0.00444

AC XY:

329

AN XY:

74056

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41456

American (AMR)

AF:

0.0118

AC:

178

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00579

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00627

AC:

424

AN:

67620

Other (OTH)

AF:

0.00808

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00549

Hom.:

Bravo

AF:

0.00570

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00400

AC:

485

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a single heterozygous variant or with a second SI variant, phase unknown, in patients with functional gastrointestinal disorders and abnormal sucrase activity from duodenal biopsy (PMID: 32732636); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 37790351, 36878682, 32732636, 29408290, 31331993, 37349966)

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SI: BP4, BS1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sucrase-isomaltase deficiency

Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Feb 28, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SI-related disorder

Benign:1

Sep 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.076

MutationAssessor

Pathogenic

3.7

PhyloP100

3.7

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.51

Sift

Uncertain

0.014

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.64

MVP

0.95

MPC

0.24

ClinPred

0.051

GERP RS

5.2

Varity_R

0.42

gMVP

0.75

Mutation Taster

=74/26

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over