NM_001041.4:c.5234T>G

Variant names:

• chr3-164983015-A-C
• rs79717168
• NM_001041.4:c.5234T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PS3 PP5 BS1_Supporting BS2

The NM_001041.4(SI):​c.5234T>G​(p.Phe1745Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,548,244 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000441942: Functional studies using COS cells transfected with wild type or variant SI plasmids demonstrated that the p.Phe1745Cys variant disrupts the trafficking of the SI protein out of the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase domain of the SI protein (Alfalah et al. 2009)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 4.29
• Publications: 16 publications found

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

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000441942: Functional studies using COS cells transfected with wild type or variant SI plasmids demonstrated that the p.Phe1745Cys variant disrupts the trafficking of the SI protein out of the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase domain of the SI protein (Alfalah et al. 2009).; SCV004046296: Functional studies showed that the c.5234T>G (p.Phe1745Cys) variant resulted in protein misfolding (PMID: 19121318, 25525159).; SCV007097108: "This variant has moderate functional evidence supporting abnormal protein function. Transfected COS-1 cells show this variant interferes with SI processing causing it to remain in the immature mannose-rich form localised in the endoplasmic reticulum. This variant also alters folding of the sucrase subunit making it unstable and inactive, while the isomaltase subunit remans intact (PMID: 19121318);"; SCV000616877: Published functional studies demonstrate a damaging effect: reduced enzymatic activity and abnormal localization (PMID: 19121318, 28062276); SCV004115976: An analysis of the SI protein showed that the p.Phe1745Cys variant altered protein folding and abolished sucrase and isomaltase/palatinase activity (Alfalah et al. 2009. PubMed ID: 19121318; Gericke et al. 2017. PubMed ID: 28062276).
• PP5: Variant 3-164983015-A-C is Pathogenic according to our data. Variant chr3-164983015-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1417.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (161/152260) while in subpopulation NFE AF = 0.00178 (121/68012). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 76 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 4 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.5234T>G	p.Phe1745Cys	missense	Exon 46 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.5234T>G	p.Phe1745Cys	missense	Exon 46 of 48	ENSP00000264382.3	P14410

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000965 AC: 241 AN: 249678 AF XY: 0.000969

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00136 AC: 1905 AN: 1395984 Hom.: 4 Cov.: 29 AF XY: 0.00127 AC XY: 876 AN XY: 692208

African (AFR) AF: 0.000155 AC: 5 AN: 32330

American (AMR) AF: 0.000514 AC: 22 AN: 42762

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 54 AN: 24766

East Asian (EAS) AF: 0.00 AC: 0 AN: 37984

South Asian (SAS) AF: 0.00 AC: 0 AN: 85200

European-Finnish (FIN) AF: 0.000405 AC: 20 AN: 49394

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5456

European-Non Finnish (NFE) AF: 0.00161 AC: 1705 AN: 1060870

Other (OTH) AF: 0.00171 AC: 98 AN: 57222

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74458

African (AFR) AF: 0.000433 AC: 18 AN: 41564

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.00100

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000948 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.000951

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	Sucrase-isomaltase deficiency (6)
1	1	-	not provided (2)
1	-	-	SI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.00029	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.98
MPC		0.060
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.74
gMVP		0.85
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs79717168; hg19: chr3-164700803;