rs183903070

Variant names:

• chr19-804442-C-T
• rs183903070
• NM_002819.5:c.435+4C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002819.5(PTBP1):​c.435+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,609,210 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: PTBP1 NM_002819.5 splice_region, intron
• Scores: Splicing: ADA: 0.001089
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.123
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042560995).
• BP6: Variant 19-804442-C-T is Benign according to our data. Variant chr19-804442-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 726561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTBP1	NM_002819.5	c.435+4C>T		splice_region_variant, intron_variant	Intron 5 of 14	ENST00000356948.11	NP_002810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTBP1	ENST00000356948.11	c.435+4C>T		splice_region_variant, intron_variant	Intron 5 of 14	1	NM_002819.5	ENSP00000349428.4

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152238 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000756 AC: 184 AN: 243430 AF XY: 0.000943

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.000495

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.000368 AC: 536 AN: 1456856 Hom.: 6 Cov.: 36 AF XY: 0.000490 AC XY: 355 AN XY: 724872

African (AFR) AF: 0.000150 AC: 5 AN: 33434

American (AMR) AF: 0.000560 AC: 25 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26068

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39690

South Asian (SAS) AF: 0.00454 AC: 391 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49870

Middle Eastern (MID) AF: 0.00137 AC: 7 AN: 5120

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111620

Other (OTH) AF: 0.000581 AC: 35 AN: 60258

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152354 Hom.: 1 Cov.: 34 AF XY: 0.000537 AC XY: 40 AN XY: 74498

African (AFR) AF: 0.000361 AC: 15 AN: 41580

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000742 AC: 90

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.93
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0043	T
PhyloP100		0.12
Sift4G	Benign	0.19	T
Vest4		0.16
GERP RS		-2.5
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.060		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: rs183903070; hg19: chr19-804442; COSMIC: COSV107439075; COSMIC: COSV107439075;