NM_001286581.2:c.166G>C

Variant names:

• chr11-582033-G-C
• rs376068613
• NM_001286581.2:c.166G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286581.2(PHRF1):​c.166G>C​(p.Gly56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHRF1 NM_001286581.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047124118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286581.2. 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
	PHRF1	NM_001286581.2	MANE Select	c.166G>C	p.Gly56Arg	missense	Exon 3 of 18	NP_001273510.1	Q9P1Y6-1
	PHRF1	NM_020901.4		c.166G>C	p.Gly56Arg	missense	Exon 3 of 18	NP_065952.2	Q9P1Y6-3
	PHRF1	NM_001286582.2		c.163G>C	p.Gly55Arg	missense	Exon 3 of 18	NP_001273511.1	F8WEF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHRF1	ENST00000264555.10	TSL:1 MANE Select	c.166G>C	p.Gly56Arg	missense	Exon 3 of 18	ENSP00000264555.5	Q9P1Y6-1
	PHRF1	ENST00000416188.3	TSL:1	c.166G>C	p.Gly56Arg	missense	Exon 3 of 18	ENSP00000410626.2	Q9P1Y6-3
	PHRF1	ENST00000413872.6	TSL:1	c.163G>C	p.Gly55Arg	missense	Exon 3 of 18	ENSP00000388589.2	F8WEF5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236778 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000137 AC: 2 AN: 1455118 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723062

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

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.0000457 AC: 2 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 84634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109072

Other (OTH) AF: 0.00 AC: 0 AN: 60154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.15	T
Polyphen		0.0060	B
Vest4		0.10
MutPred		0.27		Loss of glycosylation at T54 (P = 0.4938)
MVP		0.12
MPC		0.14
ClinPred		0.041	T
GERP RS		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.088
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs376068613; hg19: chr11-582033;