19-797498-A-G

Variant names:

• chr19-797498-A-G
• rs2145008460
• NM_002819.5:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_002819.5(PTBP1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PTBP1 NM_002819.5 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

Genes affected

PTBP1 (HGNC:9583): (polypyrimidine tract binding protein 1) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has four repeats of quasi-RNA recognition motif (RRM) domains that bind RNAs. This protein binds to the intronic polypyrimidine tracts that requires pre-mRNA splicing and acts via the protein degradation ubiquitin-proteasome pathway. It may also promote the binding of U2 snRNP to pre-mRNAs. This protein is localized in the nucleoplasm and it is also detected in the perinucleolar structure. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 31 codons. Genomic position: 803612. Lost 0.054 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTBP1	NM_002819.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENST00000356948.11	NP_002810.1
PTBP1	NM_031990.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 15		NP_114367.1
PTBP1	NM_031991.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 14		NP_114368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTBP1	ENST00000356948.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	1	NM_002819.5	ENSP00000349428.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422144 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30102

American (AMR) AF: 0.00 AC: 0 AN: 42044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35778

South Asian (SAS) AF: 0.00 AC: 0 AN: 82890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44324

Middle Eastern (MID) AF: 0.000204 AC: 1 AN: 4912

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098222

Other (OTH) AF: 0.00 AC: 0 AN: 58692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.010	.;.;T;T;.;T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PROVEAN	Benign	-0.91	N;.;.;N;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;.;.;D;D;.
Sift4G	Uncertain	0.037	D;D;T;D;D;D
Polyphen		0.012, 0.0020	.;.;.;B;B;.
Vest4		0.70
MutPred		1.0		Loss of stability (P = 0.16);Loss of stability (P = 0.16);Loss of stability (P = 0.16);Loss of stability (P = 0.16);Loss of stability (P = 0.16);Loss of stability (P = 0.16);
MVP		0.99
ClinPred		0.98	D
GERP RS		4.6
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.78
gMVP		0.32
Mutation Taster		=23/177	disease causing

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: rs2145008460; hg19: chr19-797498;