19-804613-G-A

Position:

• chr19-804613-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002819.5(PTBP1):​c.517G>A​(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,612,492 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: PTBP1 NM_002819.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.54

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008741975).
• BP6: Variant 19-804613-G-A is Benign according to our data. Variant chr19-804613-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 721042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTBP1	NM_002819.5	c.517G>A	p.Ala173Thr	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.517G>A	p.Ala173Thr	missense_variant	6/15	1	NM_002819.5	ENSP00000349428	P2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00144 AC: 356 AN: 247870 Hom.: 1 AF XY: 0.00141 AC XY: 190 AN XY: 134760

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000993

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00134 AC: 1959 AN: 1460122 Hom.: 4 Cov.: 35 AF XY: 0.00137 AC XY: 995 AN XY: 726426

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.00372

Gnomad4 FIN exome AF: 0.000672

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152370 Hom.: 0 Cov.: 34 AF XY: 0.00132 AC XY: 98 AN XY: 74504

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.00127

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00190

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.10	.;.;T;.;.;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0087	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.38	N;.;N;.;N;.;.
REVEL	Benign	0.071
Sift	Benign	0.61	T;.;T;.;T;.;.
Sift4G	Benign	0.41	T;T;T;T;T;T;T
Polyphen		0.0050, 0.0090	.;.;B;.;B;.;.
Vest4		0.39
MVP		0.65
MPC		0.45
ClinPred		0.0080	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.084
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

LitVar

Other links and lift over

dbSNP: rs150661031; hg19: chr19-804613;