chr10-23192645-G-A

Position:

• chr10-23192645-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178161.3(PTF1A):​c.115G>A​(p.Gly39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,449,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PTF1A NM_178161.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.574

Genes affected

PTF1A (HGNC:23734): (pancreas associated transcription factor 1a) This gene encodes a protein that is a component of the pancreas transcription factor 1 complex (PTF1) and is known to have a role in mammalian pancreatic development. The protein plays a role in determining whether cells allocated to the pancreatic buds continue towards pancreatic organogenesis or revert back to duodenal fates. The protein is thought to be involved in the maintenance of exocrine pancreas-specific gene expression including elastase 1 and amylase. Mutations in this gene cause cerebellar agenesis and loss of expression is seen in ductal type pancreas cancers. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09421405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTF1A	NM_178161.3	c.115G>A	p.Gly39Ser	missense_variant	1/2	ENST00000376504.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTF1A	ENST00000376504.4	c.115G>A	p.Gly39Ser	missense_variant	1/2	1	NM_178161.3	P1
PTF1A	ENST00000638469.1	c.82G>A	p.Gly28Ser	missense_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237280 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1449528 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 721088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.22
Sift	Benign	0.14	T;.
Sift4G	Uncertain	0.055	T;.
Polyphen		0.0020	B;.
Vest4		0.12
MutPred		0.12		Gain of phosphorylation at G39 (P = 0.0082);.;
MVP		0.27
ClinPred		0.24	T
GERP RS		2.0
Varity_R		0.086
gMVP		0.11

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: rs1192341489; hg19: chr10-23481574;