10-70597879-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001083116.3(PRF1):​c.*174T>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 0.0102 in 747,346 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0092 ( 11 hom., cov: 32)
Exomes 𝑓: 0.010 ( 62 hom. )

Consequence

PRF1
NM_001083116.3 3_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.636
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 10-70597879-A-G is Benign according to our data. Variant chr10-70597879-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 879864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-70597879-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00918 (1396/152024) while in subpopulation NFE AF= 0.0142 (968/67964). AF 95% confidence interval is 0.0135. There are 11 homozygotes in gnomad4. There are 679 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRF1NM_001083116.3 linkuse as main transcriptc.*174T>C 3_prime_UTR_variant 3/3 ENST00000441259.2
PRF1NM_005041.6 linkuse as main transcriptc.*174T>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.*174T>C 3_prime_UTR_variant 3/35 NM_001083116.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00920
AC:
1397
AN:
151906
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00278
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.00413
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00373
Gnomad FIN
AF:
0.0204
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0142
Gnomad OTH
AF:
0.00526
GnomAD4 exome
AF:
0.0104
AC:
6211
AN:
595322
Hom.:
62
Cov.:
8
AF XY:
0.0102
AC XY:
3172
AN XY:
311636
show subpopulations
Gnomad4 AFR exome
AF:
0.00264
Gnomad4 AMR exome
AF:
0.00385
Gnomad4 ASJ exome
AF:
0.000709
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00333
Gnomad4 FIN exome
AF:
0.0224
Gnomad4 NFE exome
AF:
0.0126
Gnomad4 OTH exome
AF:
0.00839
GnomAD4 genome
AF:
0.00918
AC:
1396
AN:
152024
Hom.:
11
Cov.:
32
AF XY:
0.00914
AC XY:
679
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00277
Gnomad4 AMR
AF:
0.00412
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00352
Gnomad4 FIN
AF:
0.0204
Gnomad4 NFE
AF:
0.0142
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.0120
Hom.:
0
Bravo
AF:
0.00769
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
1.0
DANN
Benign
0.39

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: rs74513535; hg19: chr10-72357635; API