NM_001083116.3:c.*174T>C

Variant names:

• chr10-70597879-A-G
• rs74513535
• NM_001083116.3:c.*174T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.636
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 879864.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083116.3. 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
	PRF1	NM_001083116.3	MANE Select	c.*174T>C		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*174T>C		3_prime_UTR	Exon 3 of 3	NP_005032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.*174T>C		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*174T>C		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*174T>C		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1397 AN: 151906 Hom.: 11 Cov.: 32

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

African (AFR) AF: 0.00264 AC: 39 AN: 14748

American (AMR) AF: 0.00385 AC: 82 AN: 21320

Ashkenazi Jewish (ASJ) AF: 0.000709 AC: 12 AN: 16920

East Asian (EAS) AF: 0.00 AC: 0 AN: 31816

South Asian (SAS) AF: 0.00333 AC: 181 AN: 54274

European-Finnish (FIN) AF: 0.0224 AC: 708 AN: 31540

Middle Eastern (MID) AF: 0.000852 AC: 2 AN: 2348

European-Non Finnish (NFE) AF: 0.0126 AC: 4926 AN: 391230

Other (OTH) AF: 0.00839 AC: 261 AN: 31126

GnomAD4 genome AF: 0.00918 AC: 1396 AN: 152024 Hom.: 11 Cov.: 32 AF XY: 0.00914 AC XY: 679 AN XY: 74312

African (AFR) AF: 0.00277 AC: 115 AN: 41478

American (AMR) AF: 0.00412 AC: 63 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.0204 AC: 214 AN: 10508

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

European-Non Finnish (NFE) AF: 0.0142 AC: 968 AN: 67964

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.0120 Hom.: 0

Bravo AF: 0.00769

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hemophagocytic lymphohistiocytosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.39
PhyloP100		-0.64
Mutation Taster		=100/0	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: rs74513535; hg19: chr10-72357635;