chr11-591433-T-G

Position:

• chr11-591433-T-G

Variant summary

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

The NM_001286581.2(PHRF1):​c.470T>G​(p.Ile157Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PHRF1 NM_001286581.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99

Genes affected

PHRF1 (HGNC:24351): (PHD and ring finger domains 1) Predicted to enable RNA polymerase binding activity. Predicted to be involved in mRNA processing and transcription by RNA polymerase II. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHRF1	NM_001286581.2	c.470T>G	p.Ile157Ser	missense_variant	5/18	ENST00000264555.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHRF1	ENST00000264555.10	c.470T>G	p.Ile157Ser	missense_variant	5/18	1	NM_001286581.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457438 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.470T>G (p.I157S) alteration is located in exon 5 (coding exon 4) of the PHRF1 gene. This alteration results from a T to G substitution at nucleotide position 470, causing the isoleucine (I) at amino acid position 157 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;.
Eigen	Benign	-0.0071
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.0	M;.;.;M
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.73	P;P;P;P
Vest4		0.74
MutPred		0.45		Gain of catalytic residue at I157 (P = 0.0533);.;.;Gain of catalytic residue at I157 (P = 0.0533);
MVP		0.55
MPC		0.47
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.78

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: rs1210504234; hg19: chr11-591433;