3-165067377-T-C

Variant names:

• chr3-165067377-T-C
• rs113903766
• NM_001041.4:c.598A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001041.4(SI):​c.598A>G​(p.Ser200Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,611,914 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (34 hom.)
• Consequence: SI NM_001041.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.909
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-165067377-T-C is Benign according to our data. Variant chr3-165067377-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376957.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 = 0.0113 (1719/152176) while in subpopulation AFR AF = 0.0386 (1604/41554). AF 95% confidence interval is 0.037. There are 31 homozygotes in GnomAd4. There are 817 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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.598A>G	p.Ser200Gly	missense	Exon 6 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.598A>G	p.Ser200Gly	missense	Exon 6 of 48	ENSP00000264382.3	P14410

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1703 AN: 152058 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00959

GnomAD2 exomes AF: 0.00279 AC: 700 AN: 251092 AF XY: 0.00206

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00114 AC: 1662 AN: 1459738 Hom.: 34 Cov.: 30 AF XY: 0.000994 AC XY: 722 AN XY: 726208

African (AFR) AF: 0.0378 AC: 1263 AN: 33416

American (AMR) AF: 0.00235 AC: 105 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5752

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1110616

Other (OTH) AF: 0.00315 AC: 190 AN: 60286

GnomAD4 genome AF: 0.0113 AC: 1719 AN: 152176 Hom.: 31 Cov.: 32 AF XY: 0.0110 AC XY: 817 AN XY: 74394

African (AFR) AF: 0.0386 AC: 1604 AN: 41554

American (AMR) AF: 0.00530 AC: 81 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67950

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.00421 Hom.: 18

Bravo AF: 0.0121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00354 AC: 430

Asia WGS AF: 0.00289 AC: 10 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Sucrase-isomaltase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.48
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.91
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.086
Sift	Benign	0.46	T
Sift4G	Benign	0.89	T
Polyphen		0.029	B
Vest4		0.21
MVP		0.46
MPC		0.028
ClinPred		0.012	T
GERP RS		2.7
Varity_R		0.31
gMVP		0.71
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -27

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

Other links and lift over

dbSNP: rs113903766; hg19: chr3-164785165; COSMIC: COSV99071721; COSMIC: COSV99071721;