rs535090775

Variant names:

• chr10-23192799-G-A
• rs535090775
• NM_178161.3:c.269G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-23192799-G-A
• chr10-23192799-G-C
• chr10-23192799-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178161.3(PTF1A):​c.269G>A​(p.Gly90Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000086 in 1,163,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G90A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: PTF1A NM_178161.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• pancreatic agenesis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• permanent neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• pancreatic agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21979335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178161.3. 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
	PTF1A	NM_178161.3	MANE Select	c.269G>A	p.Gly90Asp	missense	Exon 1 of 2	NP_835455.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTF1A	ENST00000376504.4	TSL:1 MANE Select	c.269G>A	p.Gly90Asp	missense	Exon 1 of 2	ENSP00000365687.3
	PTF1A	ENST00000638469.1	TSL:5	c.114+122G>A		intron	N/A	ENSP00000491649.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.60e-7 AC: 1 AN: 1163460 Hom.: 0 Cov.: 32 AF XY: 0.00000179 AC XY: 1 AN XY: 560078

African (AFR) AF: 0.00 AC: 0 AN: 23682

American (AMR) AF: 0.0000955 AC: 1 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16198

East Asian (EAS) AF: 0.00 AC: 0 AN: 26850

South Asian (SAS) AF: 0.00 AC: 0 AN: 38716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970360

Other (OTH) AF: 0.00 AC: 0 AN: 47484

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.086
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.074	B
Vest4		0.19
MutPred		0.26		Loss of catalytic residue at G88 (P = 0.1092)
MVP		0.37
ClinPred		0.11	T
GERP RS		1.9
PromoterAI		-0.040	Neutral
Varity_R		0.092
gMVP		0.35
Mutation Taster		=97/3	polymorphism

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: rs535090775; hg19: chr10-23481728;