chr10-23192574-C-T

Position:

chr10-23192574-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_178161.3(PTF1A):c.44C>T(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,601,570 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

PTF1A
NM_178161.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.48

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0110473335).

BP6

Variant 10-23192574-C-T is Benign according to our data. Variant chr10-23192574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451673.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000197 (30/152200) while in subpopulation SAS AF= 0.00145 (7/4828). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTF1A	NM_178161.3 linkuse as main transcript	c.44C>T	p.Ala15Val	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.44C>T	p.Ala15Val	missense_variant	1/2	1	NM_178161.3	P1
PTF1A	ENST00000638469.1 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000694

AC:

164

AN:

236464

Hom.:

AF XY:

0.000839

AC XY:

108

AN XY:

128778

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.00382

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000198

Gnomad OTH exome

AF:

0.00105

GnomAD4 exome

AF:

0.000386

AC:

560

AN:

1449370

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

343

AN XY:

721020

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.0000456

Gnomad4 ASJ exome

AF:

0.00349

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000133

Gnomad4 OTH exome

AF:

0.000651

GnomAD4 genome

AF:

0.000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000601

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 20, 2023	- -

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome;C4014737:Pancreatic agenesis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 27, 2022

- -

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.94

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0090

D;.

Polyphen

0.084

B;.

Vest4

0.17

MVP

0.50

ClinPred

0.044

GERP RS

3.0

Varity_R

0.25

gMVP

0.36

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