dbSNP rs758287074: SI:p.Pro758Leu (chr3-165039106-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001041.4(SI):c.2273C>T(p.Pro758Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P758H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SI
NM_001041.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.33

Publications

0 publications found

Variant links:

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: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SI	NM_001041.4 link	c.2273C>T	p.Pro758Leu	missense_variant	Exon 20 of 48	ENST00000264382.8	NP_001032.2	P14410
SI	XM_047448735.1 link	c.2273C>T	p.Pro758Leu	missense_variant	Exon 21 of 49		XP_047304691.1
SI	XM_047448736.1 link	c.2273C>T	p.Pro758Leu	missense_variant	Exon 21 of 49		XP_047304692.1
SI	XM_011513078.3 link	c.2174C>T	p.Pro725Leu	missense_variant	Exon 19 of 47		XP_011511380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SI	ENST00000264382.8 link	c.2273C>T	p.Pro758Leu	missense_variant	Exon 20 of 48	1	NM_001041.4	ENSP00000264382.3		P14410

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442804

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718894

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33058

American (AMR)

AF:

0.00

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.00

AC:

AN:

39296

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096258

Other (OTH)

AF:

0.00

AC:

AN:

59660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.3

PhyloP100

6.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-9.5

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MutPred

0.91

Gain of catalytic residue at P758 (P = 0.0262);

MVP

0.99

MPC

0.23

ClinPred

1.0

GERP RS

5.1

Varity_R

0.97

gMVP

0.98

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over