10-23192702-C-T

Position:

chr10-23192702-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178161.3(PTF1A):c.172C>T(p.His58Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,579,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

PTF1A
NM_178161.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:1

Conservation

PhyloP100: 1.64

Variant links:

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]

PTF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.24049488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTF1A	NM_178161.3 linkuse as main transcript	c.172C>T	p.His58Tyr	missense_variant	1/2	ENST00000376504.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTF1A	ENST00000376504.4 linkuse as main transcript	c.172C>T	p.His58Tyr	missense_variant	1/2	1	NM_178161.3	P1
PTF1A	ENST00000638469.1 linkuse as main transcript	c.114+25C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000237

AC:

AN:

210758

Hom.:

AF XY:

0.0000172

AC XY:

AN XY:

116362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000727

Gnomad SAS exome

AF:

0.000108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1427534

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

710164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.000156

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000546

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 03, 2021

This variant is present in population databases (rs759962056, ExAC 0.02%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PTF1A-related conditions. This sequence change replaces histidine with tyrosine at codon 58 of the PTF1A protein (p.His58Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.048

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.060

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.98

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

0.85

Vest4

0.26

MutPred

0.26

Loss of disorder (P = 0.0638);

MVP

0.68

ClinPred

0.25

GERP RS

2.9

Varity_R

0.39

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over