10-23192692-C-T

Position:

• chr10-23192692-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_178161.3(PTF1A):​c.162C>T​(p.Ser54=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,588,030 control chromosomes in the GnomAD database, including 118 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 0.0025 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (111 hom.)
• Consequence: PTF1A NM_178161.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.61

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-23192692-C-T is Benign according to our data. Variant chr10-23192692-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 299622.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00254 (386/152166) while in subpopulation EAS AF= 0.0365 (188/5154). AF 95% confidence interval is 0.0322. There are 7 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTF1A	NM_178161.3	c.162C>T	p.Ser54=	synonymous_variant	1/2	ENST00000376504.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTF1A	ENST00000376504.4	c.162C>T	p.Ser54=	synonymous_variant	1/2	1	NM_178161.3	P1
PTF1A	ENST00000638469.1	c.114+15C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152056 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0362

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00734 AC: 1609 AN: 219074 Hom.: 37 AF XY: 0.00829 AC XY: 1000 AN XY: 120606

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.000287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0398

Gnomad SAS exome AF: 0.0344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000499

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00294 AC: 4221 AN: 1435864 Hom.: 111 Cov.: 33 AF XY: 0.00375 AC XY: 2677 AN XY: 714432

Gnomad4 AFR exome AF: 0.000224

Gnomad4 AMR exome AF: 0.000187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0313

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000281

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152166 Hom.: 7 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74386

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.0342

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000967 Hom.: 1

Bravo AF: 0.00181

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neonatal insulin-dependent diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

PTF1A gene is associated with neonatal onset diabetes due to pancreatic aplasia, leading to insulin dependence. It is associated with extra pancreatic manifestation of neurological impairment. However, the role of this particulat variant (rs117678424) in neonatal diabetes is yet to be ascertained. -

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

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Uncertain	0.98

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: rs117678424; hg19: chr10-23481621;