3-164982253-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001041.4(SI):c.5405C>G(p.Thr1802Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,611,810 control chromosomes in the GnomAD database, including 1,164 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (606 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (558 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.10

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001375407).
• BP6: Variant 3-164982253-G-C is Benign according to our data. Variant chr3-164982253-G-C is described in ClinVar as [Benign]. Clinvar id is 343999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SI	NM_001041.4	c.5405C>G	p.Thr1802Ser	missense_variant	47/48	ENST00000264382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SI	ENST00000264382.8	c.5405C>G	p.Thr1802Ser	missense_variant	47/48	1	NM_001041.4	P1

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7337 AN: 152060 Hom.: 604 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0128 AC: 3214 AN: 250200 Hom.: 244 AF XY: 0.00918 AC XY: 1241 AN XY: 135258

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.00560

GnomAD4 exome AF: 0.00510 AC: 7440 AN: 1459632 Hom.: 558 Cov.: 30 AF XY: 0.00428 AC XY: 3105 AN XY: 726242

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.00998

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0483 AC: 7350 AN: 152178 Hom.: 606 Cov.: 32 AF XY: 0.0459 AC XY: 3417 AN XY: 74400

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.00782 Hom.: 63

Bravo AF: 0.0564

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.163 AC: 718

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0155 AC: 1877

Asia WGS AF: 0.0160 AC: 57 AN: 3474

EpiCase AF: 0.000764

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Sucrase-isomaltase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.0010
Dann	Benign	0.13
DEOGEN2	Benign	0.015	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.063	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.25
Sift	Benign	0.80	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.29		Loss of sheet (P = 0.0457);
MPC		0.027
ClinPred		0.0019	T
GERP RS		-8.7
Varity_R		0.022
gMVP		0.21

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: rs9917722; hg19: chr3-164700041;