chr19-804560-A-G

Position:

• chr19-804560-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002819.5(PTBP1):​c.464A>G​(p.Asn155Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PTBP1 NM_002819.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21

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

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=0.1720224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTBP1	NM_002819.5	c.464A>G	p.Asn155Ser	missense_variant	6/15	ENST00000356948.11	NP_002810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTBP1	ENST00000356948.11	c.464A>G	p.Asn155Ser	missense_variant	6/15	1	NM_002819.5	ENSP00000349428	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455588 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 724124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.464A>G (p.N155S) alteration is located in exon 6 (coding exon 6) of the PTBP1 gene. This alteration results from a A to G substitution at nucleotide position 464, causing the asparagine (N) at amino acid position 155 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.68
DEOGEN2	Benign	0.13	.;.;T;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;D;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;.;N;.;N;.;.
REVEL	Benign	0.061
Sift	Benign	0.60	T;.;T;.;T;.;.
Sift4G	Benign	0.79	T;T;T;T;T;T;T
Polyphen		0.025, 0.0010	.;.;B;.;B;.;.
Vest4		0.31
MutPred		0.22		Gain of disorder (P = 0.0853);.;Gain of disorder (P = 0.0853);.;Gain of disorder (P = 0.0853);.;.;
MVP		0.76
MPC		0.37
ClinPred		0.79	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-804560;