chr10-70598007-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001083116.3(PRF1):​c.*46T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,603,938 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

PRF1
NM_001083116.3 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.250
Variant links:
Genes affected
PRF1 (HGNC:9360): (perforin 1) This gene encodes a protein with structural similarities to complement component C9 that is important in immunity. This protein forms membrane pores that allow the release of granzymes and subsequent cytolysis of target cells. Whether pore formation occurs in the plasma membrane of target cells or in an endosomal membrane inside target cells is subject to debate. Mutations in this gene are associated with a variety of human disease including diabetes, multiple sclerosis, lymphomas, autoimmune lymphoproliferative syndrome (ALPS), aplastic anemia, and familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of early childhood. [provided by RefSeq, Aug 2017]
PALD1 (HGNC:23530): (phosphatase domain containing paladin 1) Predicted to enable protein tyrosine phosphatase activity. Predicted to be involved in peptidyl-tyrosine dephosphorylation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (436/152210) while in subpopulation AMR AF= 0.00484 (74/15280). AF 95% confidence interval is 0.00396. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRF1NM_001083116.3 linkuse as main transcriptc.*46T>C 3_prime_UTR_variant 3/3 ENST00000441259.2
PRF1NM_005041.6 linkuse as main transcriptc.*46T>C 3_prime_UTR_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRF1ENST00000441259.2 linkuse as main transcriptc.*46T>C 3_prime_UTR_variant 3/35 NM_001083116.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00287
AC:
436
AN:
152092
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00485
Gnomad ASJ
AF:
0.0104
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00113
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00412
Gnomad OTH
AF:
0.00527
GnomAD3 exomes
AF:
0.00311
AC:
757
AN:
243542
Hom.:
2
AF XY:
0.00322
AC XY:
426
AN XY:
132174
show subpopulations
Gnomad AFR exome
AF:
0.000441
Gnomad AMR exome
AF:
0.00377
Gnomad ASJ exome
AF:
0.0101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000426
Gnomad FIN exome
AF:
0.00120
Gnomad NFE exome
AF:
0.00407
Gnomad OTH exome
AF:
0.00479
GnomAD4 exome
AF:
0.00316
AC:
4588
AN:
1451728
Hom.:
11
Cov.:
32
AF XY:
0.00317
AC XY:
2290
AN XY:
722616
show subpopulations
Gnomad4 AFR exome
AF:
0.000598
Gnomad4 AMR exome
AF:
0.00387
Gnomad4 ASJ exome
AF:
0.0103
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000430
Gnomad4 FIN exome
AF:
0.00160
Gnomad4 NFE exome
AF:
0.00339
Gnomad4 OTH exome
AF:
0.00369
GnomAD4 genome
AF:
0.00286
AC:
436
AN:
152210
Hom.:
1
Cov.:
32
AF XY:
0.00288
AC XY:
214
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.000530
Gnomad4 AMR
AF:
0.00484
Gnomad4 ASJ
AF:
0.0104
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00113
Gnomad4 NFE
AF:
0.00412
Gnomad4 OTH
AF:
0.00522
Alfa
AF:
0.00440
Hom.:
0
Bravo
AF:
0.00344
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.94
DANN
Benign
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140956842; hg19: chr10-72357763; API