19-54115693-G-C

Variant names:

• chr19-54115693-G-C
• rs17526361
• ENST00000419967.5:c.-113G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000419967.5(PRPF31):​c.-113G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 330,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: PRPF31 ENST00000419967.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594
• Publications: 2 publications found

Genes affected

PRPF31 (HGNC:15446): (pre-mRNA processing factor 31) This gene encodes a component of the spliceosome complex and is one of several retinitis pigmentosa-causing genes. When the gene product is added to the spliceosome complex, activation occurs.[provided by RefSeq, Jan 2009]

TFPT (HGNC:13630): (TCF3 fusion partner) Predicted to enable DNA binding activity and protein kinase binding activity. Involved in apoptotic signaling pathway. Located in nucleoplasm. Part of Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000591 (9/152298) while in subpopulation EAS AF = 0.00155 (8/5178). AF 95% confidence interval is 0.000768. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000419967.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF31	NM_015629.4	MANE Select	c.-113G>C		upstream_gene	N/A	NP_056444.3
	TFPT	NM_013342.4	MANE Select	c.-424C>G		upstream_gene	N/A	NP_037474.1	P0C1Z6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF31	ENST00000419967.5	TSL:5	c.-113G>C		5_prime_UTR	Exon 1 of 13	ENSP00000405166.2	Q8WWY3-4
	PRPF31	ENST00000321030.9	TSL:1 MANE Select	c.-113G>C		upstream_gene	N/A	ENSP00000324122.4	Q8WWY3-1
	TFPT	ENST00000391759.6	TSL:1 MANE Select	c.-424C>G		upstream_gene	N/A	ENSP00000375639.1	P0C1Z6-1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000651 AC: 116 AN: 178288 Hom.: 0 Cov.: 0 AF XY: 0.000581 AC XY: 52 AN XY: 89502

African (AFR) AF: 0.00 AC: 0 AN: 6696

American (AMR) AF: 0.00 AC: 0 AN: 6632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7358

East Asian (EAS) AF: 0.00749 AC: 113 AN: 15094

South Asian (SAS) AF: 0.00 AC: 0 AN: 16356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 822

European-Non Finnish (NFE) AF: 0.00000927 AC: 1 AN: 107854

Other (OTH) AF: 0.000169 AC: 2 AN: 11830

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.57
PhyloP100		0.59
PromoterAI		-0.13	Neutral

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: rs17526361; hg19: chr19-54619073;