rs45619231

Variant names:

• chr19-54115619-C-A
• rs45619231
• NM_013342.4:c.-350G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_013342.4(TFPT):​c.-350G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 428,626 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (5 hom.)
• Consequence: TFPT NM_013342.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.648
• Publications: 3 publications found

Genes affected

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]

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]

PRPF31 Gene-Disease associations (from GenCC):

• PRPF31-related retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-54115619-C-A is Benign according to our data. Variant chr19-54115619-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330087.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013342.4. 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
	TFPT	NM_013342.4	MANE Select	c.-350G>T		5_prime_UTR	Exon 1 of 6	NP_037474.1	P0C1Z6-1
	PRPF31	NM_015629.4	MANE Select	c.-187C>A		upstream_gene	N/A	NP_056444.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPT	ENST00000391759.6	TSL:1 MANE Select	c.-350G>T		5_prime_UTR	Exon 1 of 6	ENSP00000375639.1	P0C1Z6-1
	PRPF31	ENST00000419967.5	TSL:5	c.-187C>A		5_prime_UTR	Exon 1 of 13	ENSP00000405166.2	Q8WWY3-4
	TFPT	ENST00000911296.1		c.-350G>T		5_prime_UTR	Exon 1 of 6	ENSP00000581355.1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 681 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00490 AC: 1354 AN: 276264 Hom.: 5 Cov.: 0 AF XY: 0.00491 AC XY: 697 AN XY: 142032

African (AFR) AF: 0.000901 AC: 8 AN: 8880

American (AMR) AF: 0.00251 AC: 24 AN: 9550

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 10 AN: 9716

East Asian (EAS) AF: 0.00 AC: 0 AN: 21570

South Asian (SAS) AF: 0.00191 AC: 38 AN: 19874

European-Finnish (FIN) AF: 0.00126 AC: 23 AN: 18220

Middle Eastern (MID) AF: 0.00153 AC: 2 AN: 1304

European-Non Finnish (NFE) AF: 0.00689 AC: 1169 AN: 169770

Other (OTH) AF: 0.00460 AC: 80 AN: 17380

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00415 AC XY: 309 AN XY: 74516

African (AFR) AF: 0.00166 AC: 69 AN: 41594

American (AMR) AF: 0.00601 AC: 92 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4834

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00703 AC: 478 AN: 68030

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00414

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.8
DANN	Benign	0.57
PhyloP100		-0.65
PromoterAI		-0.18	Neutral
Mutation Taster		=300/0	polymorphism

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: rs45619231; hg19: chr19-54618999;