10-70598821-G-T

Position:

• chr10-70598821-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083116.3(PRF1):​c.900C>A​(p.His300Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H300H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.15

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24670362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.900C>A	p.His300Gln	missense_variant	3/3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.900C>A	p.His300Gln	missense_variant	3/3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.900C>A	p.His300Gln	missense_variant	3/3	5	NM_001083116.3	ENSP00000398568	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 106

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.18
DANN	Benign	0.80
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.29	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.85	P;P
Vest4		0.053
MutPred		0.46		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.28
MPC		0.16
ClinPred		0.88	D
GERP RS		-12
Varity_R		0.12
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs885822; hg19: chr10-72358577;