rs35947132

Variant names:

• chr10-70600631-G-A
• rs35947132
• NM_001083116.3:c.272C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70600631-G-A
• chr10-70600631-G-C
• chr10-70600631-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001083116.3(PRF1):​c.272C>T​(p.Ala91Val) variant causes a missense change. The variant allele was found at a frequency of 0.0354 in 1,613,234 control chromosomes in the GnomAD database, including 1,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. A91A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (99 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1160 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications U:5 B:10 O:2
• Conservation: PhyloP100: 6.74
• Publications: 141 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 -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.016731 (below the threshold of 3.09). Trascript score misZ: 0.68523 (below the threshold of 3.09). GenCC associations: The gene is linked to lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071359873).
• BP6: Variant 10-70600631-G-A is Benign according to our data. Variant chr10-70600631-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 13718.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0287 (4365/152350) while in subpopulation NFE AF = 0.0448 (3046/68034). AF 95% confidence interval is 0.0434. There are 99 homozygotes in GnomAd4. There are 2024 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 99 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.272C>T	p.Ala91Val	missense	Exon 2 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.272C>T	p.Ala91Val	missense	Exon 2 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.272C>T	p.Ala91Val	missense	Exon 2 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.272C>T	p.Ala91Val	missense	Exon 2 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.272C>T	p.Ala91Val	missense	Exon 1 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4362 AN: 152232 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0293 AC: 7315 AN: 249508 AF XY: 0.0299

Gnomad AFR exome AF: 0.00574

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0466

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0361 AC: 52738 AN: 1460884 Hom.: 1160 Cov.: 34 AF XY: 0.0357 AC XY: 25949 AN XY: 726634

African (AFR) AF: 0.00535 AC: 179 AN: 33460

American (AMR) AF: 0.0248 AC: 1107 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 682 AN: 26110

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39680

South Asian (SAS) AF: 0.00384 AC: 331 AN: 86210

European-Finnish (FIN) AF: 0.0305 AC: 1627 AN: 53262

Middle Eastern (MID) AF: 0.0237 AC: 134 AN: 5660

European-Non Finnish (NFE) AF: 0.0422 AC: 46856 AN: 1111488

Other (OTH) AF: 0.0301 AC: 1815 AN: 60342

GnomAD4 genome AF: 0.0287 AC: 4365 AN: 152350 Hom.: 99 Cov.: 32 AF XY: 0.0272 AC XY: 2024 AN XY: 74514

African (AFR) AF: 0.00721 AC: 300 AN: 41586

American (AMR) AF: 0.0276 AC: 423 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3046 AN: 68034

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0411 Hom.: 364

Bravo AF: 0.0291

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0413 AC: 159

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0463 AC: 398

ExAC AF: 0.0305 AC: 3707

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0489

EpiControl AF: 0.0517

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Familial hemophagocytic lymphohistiocytosis 2 (6)
-	-	5	not specified (5)
-	1	1	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Hemophagocytic lymphohistiocytosis, familial, 2, susceptibility to (1)
-	1	-	PRF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0071	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.7
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.43
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.32
gMVP		0.77
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35947132; hg19: chr10-72360387;