3-165067458-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001041.4(SI):c.517C>G(p.Pro173Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,610,858 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (32 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009579778).
• BP6: Variant 3-165067458-G-C is Benign according to our data. Variant chr3-165067458-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 445929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1928/152038) while in subpopulation AFR AF= 0.0439 (1819/41480). AF 95% confidence interval is 0.0422. There are 38 homozygotes in gnomad4. There are 941 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SI	NM_001041.4	c.517C>G	p.Pro173Ala	missense_variant	6/48	ENST00000264382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SI	ENST00000264382.8	c.517C>G	p.Pro173Ala	missense_variant	6/48	1	NM_001041.4	P1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1915 AN: 151920 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00341 AC: 857 AN: 251150 Hom.: 17 AF XY: 0.00247 AC XY: 335 AN XY: 135750

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00127 AC: 1853 AN: 1458820 Hom.: 32 Cov.: 29 AF XY: 0.00108 AC XY: 783 AN XY: 725920

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000901

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.0127 AC: 1928 AN: 152038 Hom.: 38 Cov.: 32 AF XY: 0.0127 AC XY: 941 AN XY: 74322

Gnomad4 AFR AF: 0.0439

Gnomad4 AMR AF: 0.00518

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.000947 Hom.: 1

Bravo AF: 0.0143

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00413 AC: 502

Asia WGS AF: 0.00348 AC: 12 AN: 3466

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Sucrase-isomaltase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 12, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.87
MPC		0.14
ClinPred		0.064	T
GERP RS		4.9
Varity_R		0.70
gMVP		0.63

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: rs146960446; hg19: chr3-164785246;