rs146785675

chr3-165023746-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.70

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 -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 id is 344034.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, Benign=1}. Variant chr3-165023746-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SI	NM_001041.4	c.2923T>C	p.Tyr975His	missense_variant	26/48	ENST00000264382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SI	ENST00000264382.8	c.2923T>C	p.Tyr975His	missense_variant	26/48	1	NM_001041.4	P1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 729 AN: 151416 Hom.: 8 Cov.: 32

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

GnomAD3 exomes AF: 0.00420 AC: 1049 AN: 249710 Hom.: 3 AF XY: 0.00434 AC XY: 585 AN XY: 134936

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 SAS exome AF: 0.00144

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.: 20 Cov.: 31 AF XY: 0.00505 AC XY: 3666 AN XY: 725754

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.00550

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00482 AC: 730 AN: 151534 Hom.: 8 Cov.: 32 AF XY: 0.00444 AC XY: 329 AN XY: 74056

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00579

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00627

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.00576 Hom.: 3

Bravo AF: 0.00570

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00400 AC: 485

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sucrase-isomaltase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2020	- -
Uncertain significance, 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, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SI: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

SI-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.95
MPC		0.24
ClinPred		0.051	T
GERP RS		5.2
Varity_R		0.42
gMVP		0.75

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: rs146785675; hg19: chr3-164741534;