chr10-70597843-TA-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001083116.3(PRF1):​c.*209delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (3658 hom., cov: 0)
  • Exomes 𝑓: 0.42 (57 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 -16 ACMG points.

• BP6: Variant 10-70597843-TA-T is Benign according to our data. Variant chr10-70597843-TA-T is described in ClinVar as Benign. ClinVar VariationId is 300321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

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.*209delT		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*209delT		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.*209delT		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*209delT		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*209delT		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 32862 AN: 138866 Hom.: 3658 Cov.: 0

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.198

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.419 AC: 182401 AN: 435844 Hom.: 57 Cov.: 0 AF XY: 0.418 AC XY: 95712 AN XY: 229006

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

African (AFR) AF: 0.331 AC: 3952 AN: 11940

American (AMR) AF: 0.397 AC: 7065 AN: 17778

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 5675 AN: 12932

East Asian (EAS) AF: 0.436 AC: 12361 AN: 28382

South Asian (SAS) AF: 0.397 AC: 16890 AN: 42518

European-Finnish (FIN) AF: 0.434 AC: 11940 AN: 27524

Middle Eastern (MID) AF: 0.419 AC: 793 AN: 1892

European-Non Finnish (NFE) AF: 0.423 AC: 113311 AN: 268018

Other (OTH) AF: 0.419 AC: 10414 AN: 24860

⚠️ 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: 0.237 AC: 32877 AN: 138914 Hom.: 3658 Cov.: 0 AF XY: 0.236 AC XY: 15820 AN XY: 66964

African (AFR) AF: 0.212 AC: 8086 AN: 38096

American (AMR) AF: 0.188 AC: 2567 AN: 13642

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 711 AN: 3264

East Asian (EAS) AF: 0.0256 AC: 119 AN: 4644

South Asian (SAS) AF: 0.280 AC: 1212 AN: 4322

European-Finnish (FIN) AF: 0.288 AC: 2356 AN: 8188

Middle Eastern (MID) AF: 0.215 AC: 59 AN: 274

European-Non Finnish (NFE) AF: 0.268 AC: 17047 AN: 63720

Other (OTH) AF: 0.243 AC: 466 AN: 1920

Alfa AF: 0.0937 Hom.: 140

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hemophagocytic lymphohistiocytosis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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; COSMIC: COSV64615064;