NM_000415.3:c.157A>G

Variant names:

• chr12-21378313-A-G
• rs1800203
• NM_000415.3:c.157A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000415.3(IAPP):​c.157A>G​(p.Ser53Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,220 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: IAPP NM_000415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 5 publications found

Genes affected

IAPP (HGNC:5329): (islet amyloid polypeptide) This gene encodes a member of the calcitonin family of peptide hormones. This hormone is released from pancreatic beta cells following food intake to regulate blood glucose levels and act as a satiation signal. Human patients with type 1 and advanced type 2 diabetes exhibit reduced levels of the encoded hormone in blood and pancreas. This protein also exhibits a bactericidal, antimicrobial activity. [provided by RefSeq, Jul 2016]

SLCO1A2 (HGNC:10956): (solute carrier organic anion transporter family member 1A2) This gene encodes a sodium-independent transporter which mediates cellular uptake of organic ions in the liver. Its substrates include bile acids, bromosulphophthalein, and some steroidal compounds. The protein is a member of the SLC21A family of solute carriers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009331822).
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000415.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IAPP	NM_000415.3	MANE Select	c.157A>G	p.Ser53Gly	missense	Exon 3 of 3	NP_000406.1
	IAPP	NM_001329201.2		c.157A>G	p.Ser53Gly	missense	Exon 3 of 3	NP_001316130.1
	SLCO1A2	NM_001386878.1		c.-63+25106T>C		intron	N/A	NP_001373807.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IAPP	ENST00000240652.8	TSL:1 MANE Select	c.157A>G	p.Ser53Gly	missense	Exon 3 of 3	ENSP00000240652.3
	SLCO1A2	ENST00000307378.10	TSL:1	c.-189-3788T>C		intron	N/A	ENSP00000305974.6
	IAPP	ENST00000539393.5	TSL:2	c.157A>G	p.Ser53Gly	missense	Exon 3 of 3	ENSP00000437357.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00961

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000799 AC: 201 AN: 251416 AF XY: 0.000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00995

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1461856 Hom.: 3 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.00663 AC: 263 AN: 39696

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111980

Other (OTH) AF: 0.000298 AC: 18 AN: 60396

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74518

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00944 AC: 49 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000467 Hom.: 2

Bravo AF: 0.000491

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.24
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.039	B
Vest4		0.68
MVP		0.25
MPC		0.10
ClinPred		0.040	T
GERP RS		2.6
Varity_R		0.47
gMVP		0.31
Mutation Taster		=45/55	disease causing

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: rs1800203; hg19: chr12-21531247; COSMIC: COSV99556978;