rs121912616

Variant names:

• chr3-165021265-C-T
• rs121912616
• NM_001041.4:c.3218G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-165021265-C-T
• chr3-165021265-C-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PS3 PP5 BP4 BS1_Supporting BS2

The NM_001041.4(SI):​c.3218G>A​(p.Gly1073Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,611,224 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000441975: Functional studies using COS cells transfected with wild type or variant SI plasmids demonstrated that the p.Gly1073Asp variant prevents the SI protein from exiting the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase and isomaltase domains (Alfalah et al. 2009)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:2
• Conservation: PhyloP100: 5.37
• Publications: 21 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: Likely_benign. The variant received -1 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000441975: Functional studies using COS cells transfected with wild type or variant SI plasmids demonstrated that the p.Gly1073Asp variant prevents the SI protein from exiting the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase and isomaltase domains (Alfalah et al. 2009).; SCV000967637: "In vitro functional studies of the variant report an impact to protein folding along with reduced activity." PMID:19121318; SCV001445872: Functional studies have demonstrated that the c.3218G>A (p.Gly1073Asp) variant results in protein misfolding, the inability of the protein to exit the endoplasmic reticulum, and reduced enzymatic activity (PMID: 19121318).; SCV003929118: At least two publications reports experimental evidence evaluating an impact on protein function, finding <10% of normal enzymatic activity as well as disruption of folding and transport from the endoplasmic reticulum (Alfalah_2009, Gericke_2017).; SCV004175660: Functional studies have demostrated that the variant disrupt the protein folding along with reduced enzymatic activity (PMID: 27579322, 19121318) (PS3).; SCV005398137: "In vitro studies demonstrated misfolding of the mutant protein, preventing its exit from the endoplasmic reticulum. In addition, it had markedly reduced sucrase and isomaltase enzymatic activities." PMID:19121318; SCV005350460: Functional studies in vitro suggest absence of enzymatic activity is due to protein misfolding (Alfalah et al. 2009. PubMed ID: 19121318).
• PP5: Variant 3-165021265-C-T is Pathogenic according to our data. Variant chr3-165021265-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1419.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41911948). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00149 (226/151654) while in subpopulation NFE AF = 0.00275 (186/67714). AF 95% confidence interval is 0.00242. There are 0 homozygotes in GnomAd4. There are 92 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 6 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.3218G>A	p.Gly1073Asp	missense	Exon 27 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.3218G>A	p.Gly1073Asp	missense	Exon 27 of 48	ENSP00000264382.3	P14410

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 151536 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00124 AC: 310 AN: 250488 AF XY: 0.00125

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00278 AC: 4063 AN: 1459570 Hom.: 6 Cov.: 31 AF XY: 0.00272 AC XY: 1977 AN XY: 726122

African (AFR) AF: 0.000630 AC: 21 AN: 33356

American (AMR) AF: 0.000560 AC: 25 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86224

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00346 AC: 3837 AN: 1110342

Other (OTH) AF: 0.00211 AC: 127 AN: 60258

GnomAD4 genome AF: 0.00149 AC: 226 AN: 151654 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74134

African (AFR) AF: 0.000651 AC: 27 AN: 41460

American (AMR) AF: 0.000595 AC: 9 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00275 AC: 186 AN: 67714

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00146

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00114 AC: 139

EpiCase AF: 0.00169

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
14	1	-	Sucrase-isomaltase deficiency (15)
5	1	-	not provided (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	SI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.67
MPC		0.25
ClinPred		0.14	T
GERP RS		4.6
Varity_R		0.94
gMVP		0.74
Mutation Taster		=63/37	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912616; hg19: chr3-164739053;