Genetic Variant SI:c.*121C>T (chr3-164979241-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001041.4(SI):c.*121C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 722,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SI
NM_001041.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.67

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

SI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000785 (119/151652) while in subpopulation AFR AF = 0.0026 (108/41470). AF 95% confidence interval is 0.00221. There are 0 homozygotes in GnomAd4. There are 51 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

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.*121C>T		3_prime_UTR	Exon 48 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.*121C>T		3_prime_UTR	Exon 48 of 48	ENSP00000264382.3	P14410

Frequencies

GnomAD3 genomes

AF:

0.000779

AC:

118

AN:

151534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000462

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000109

AC:

AN:

570448

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

311054

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

16522

American (AMR)

AF:

0.0000780

AC:

AN:

38442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19260

East Asian (EAS)

AF:

0.0000867

AC:

AN:

34592

South Asian (SAS)

AF:

0.00

AC:

AN:

64080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3740

European-Non Finnish (NFE)

AF:

0.0000215

AC:

AN:

325454

Other (OTH)

AF:

0.000391

AC:

AN:

30720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000785

AC:

119

AN:

151652

Hom.:

Cov.:

AF XY:

0.000688

AC XY:

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41470

American (AMR)

AF:

0.000461

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67692

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.000907

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sucrase-isomaltase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.19

(source)

DANN

Benign

0.52

PhyloP100

-1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over