10-70597843-TAAAAAA-TAAAAAAAAA

Variant names:

• chr10-70597843-T-TAAA
• rs34914326
• NM_001083116.3:c.*207_*209dupTTT

Variant summary

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

The NM_001083116.3(PRF1):​c.*207_*209dupTTT 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 0.010 (30 hom., cov: 0)
  • Exomes 𝑓: 0.00054 (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 afr. GnomAd4 allele frequency = 0.0103 (1432/139144) while in subpopulation AFR AF = 0.0361 (1376/38124). AF 95% confidence interval is 0.0345. There are 30 homozygotes in GnomAd4. There are 669 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.*207_*209dupTTT		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*207_*209dupTTT		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.*207_*209dupTTT		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*207_*209dupTTT		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*207_*209dupTTT		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1434 AN: 139096 Hom.: 30 Cov.: 0

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00286

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00336

Gnomad NFE AF: 0.0000313

Gnomad OTH AF: 0.00680

GnomAD4 exome AF: 0.000538 AC: 246 AN: 457380 Hom.: 0 Cov.: 0 AF XY: 0.000387 AC XY: 93 AN XY: 240012

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

African (AFR) AF: 0.0156 AC: 192 AN: 12270

American (AMR) AF: 0.000807 AC: 15 AN: 18588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13748

East Asian (EAS) AF: 0.00 AC: 0 AN: 31204

South Asian (SAS) AF: 0.00 AC: 0 AN: 43660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1984

European-Non Finnish (NFE) AF: 0.0000392 AC: 11 AN: 280726

Other (OTH) AF: 0.00107 AC: 28 AN: 26134

⚠️ 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: 0.0103 AC: 1432 AN: 139144 Hom.: 30 Cov.: 0 AF XY: 0.00997 AC XY: 669 AN XY: 67106

African (AFR) AF: 0.0361 AC: 1376 AN: 38124

American (AMR) AF: 0.00286 AC: 39 AN: 13658

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4650

South Asian (SAS) AF: 0.000231 AC: 1 AN: 4332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8226

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.0000313 AC: 2 AN: 63844

Other (OTH) AF: 0.00676 AC: 13 AN: 1922

Alfa AF: 0.00 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34914326; hg19: chr10-72357599;