NM_001083116.3:c.*209dupT

Variant names:

• chr10-70597843-T-TA
• rs34914326
• NM_001083116.3:c.*209dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001083116.3(PRF1):​c.*209dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 0)
  • Exomes 𝑓: 0.0069 (0 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00662 (921/139118) while in subpopulation NFE AF = 0.00976 (623/63828). AF 95% confidence interval is 0.00913. There are 7 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.*209dupT		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*209dupT		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.*209dupT		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*209dupT		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*209dupT		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 920 AN: 139070 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00451

Gnomad SAS AF: 0.000920

Gnomad FIN AF: 0.00682

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00976

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.00692 AC: 3160 AN: 456910 Hom.: 0 Cov.: 0 AF XY: 0.00690 AC XY: 1655 AN XY: 239772

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00315 AC: 39 AN: 12396

American (AMR) AF: 0.00409 AC: 76 AN: 18582

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 18 AN: 13734

East Asian (EAS) AF: 0.00401 AC: 125 AN: 31168

South Asian (SAS) AF: 0.00303 AC: 132 AN: 43608

European-Finnish (FIN) AF: 0.00530 AC: 154 AN: 29032

Middle Eastern (MID) AF: 0.00404 AC: 8 AN: 1982

European-Non Finnish (NFE) AF: 0.00867 AC: 2430 AN: 280270

Other (OTH) AF: 0.00681 AC: 178 AN: 26138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00662 AC: 921 AN: 139118 Hom.: 7 Cov.: 0 AF XY: 0.00607 AC XY: 407 AN XY: 67094

African (AFR) AF: 0.00299 AC: 114 AN: 38134

American (AMR) AF: 0.00666 AC: 91 AN: 13654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3270

East Asian (EAS) AF: 0.00452 AC: 21 AN: 4648

South Asian (SAS) AF: 0.00115 AC: 5 AN: 4332

European-Finnish (FIN) AF: 0.00682 AC: 56 AN: 8212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00976 AC: 623 AN: 63828

Other (OTH) AF: 0.00572 AC: 11 AN: 1922

Alfa AF: 0.00154 Hom.: 140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs34914326; hg19: chr10-72357599;