rs143388292

chr3-165009359-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001041.4(SI):c.4099A>G(p.Arg1367Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000337 in 1,613,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-165009359-T-C is Pathogenic according to our data. Variant chr3-165009359-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 344017.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SI	NM_001041.4	c.4099A>G	p.Arg1367Gly	missense_variant	35/48	ENST00000264382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SI	ENST00000264382.8	c.4099A>G	p.Arg1367Gly	missense_variant	35/48	1	NM_001041.4	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251028 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135682

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000338 AC: 494 AN: 1461276 Hom.: 0 Cov.: 30 AF XY: 0.000341 AC XY: 248 AN XY: 726936

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	Identified in at least one patient with irritable bowel syndrome with diarrhea in published literature (Garcia-Etxebarria et al., 2018); 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: 16329100, 29408290) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1367 of the SI protein (p.Arg1367Gly). This variant is present in population databases (rs143388292, gnomAD 0.05%). This missense change has been observed in individual(s) with sucrase-isomaltase deficiency and irritable bowel syndrome (PMID: 16329100, 29408290, 32732636). ClinVar contains an entry for this variant (Variation ID: 344017). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SI protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sucrase-isomaltase deficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SI c.4099A>G (p.Arg1367Gly) missense variant has been reported in one study in which it was found in one individual with congenital sucrase-isomaltase deficiency in a compound heterozygous state along with a frameshift variant (Sander et al. 2006). Control data are unavailable for this variant, but it is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Arg1367Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for congenital sucrose-isomaltase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.55	N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.031	D
Polyphen		0.98	D
Vest4		0.51
MVP		0.95
MPC		0.23
ClinPred		0.74	D
GERP RS		0.55
Varity_R		0.46
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs143388292; hg19: chr3-164727147;