NM_001286581.2:c.4346T>C

Variant names:

• chr11-610277-T-C
• rs11246212
• NM_001286581.2:c.4346T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286581.2(PHRF1):​c.4346T>C​(p.Val1449Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,558,542 control chromosomes in the GnomAD database, including 578,664 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (53503 hom., cov: 33)
  • Exomes 𝑓: 0.86 (525161 hom.)
• Consequence: PHRF1 NM_001286581.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764
• Publications: 33 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.809924E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHRF1	NM_001286581.2	MANE Select	c.4346T>C	p.Val1449Ala	missense	Exon 15 of 18	NP_001273510.1
	PHRF1	NM_020901.4		c.4343T>C	p.Val1448Ala	missense	Exon 15 of 18	NP_065952.2
	PHRF1	NM_001286582.2		c.4340T>C	p.Val1447Ala	missense	Exon 15 of 18	NP_001273511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHRF1	ENST00000264555.10	TSL:1 MANE Select	c.4346T>C	p.Val1449Ala	missense	Exon 15 of 18	ENSP00000264555.5
	PHRF1	ENST00000416188.3	TSL:1	c.4343T>C	p.Val1448Ala	missense	Exon 15 of 18	ENSP00000410626.2
	PHRF1	ENST00000413872.6	TSL:1	c.4340T>C	p.Val1447Ala	missense	Exon 15 of 18	ENSP00000388589.2

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127387 AN: 152092 Hom.: 53487 Cov.: 33

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.872

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.838 AC: 138858 AN: 165764 AF XY: 0.842

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.760

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.865

Gnomad NFE exome AF: 0.871

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.864 AC: 1214486 AN: 1406332 Hom.: 525161 Cov.: 70 AF XY: 0.864 AC XY: 599755 AN XY: 694520

African (AFR) AF: 0.781 AC: 24910 AN: 31890

American (AMR) AF: 0.766 AC: 28494 AN: 37176

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 23035 AN: 25312

East Asian (EAS) AF: 0.792 AC: 28744 AN: 36280

South Asian (SAS) AF: 0.836 AC: 66684 AN: 79776

European-Finnish (FIN) AF: 0.861 AC: 41812 AN: 48540

Middle Eastern (MID) AF: 0.881 AC: 5020 AN: 5696

European-Non Finnish (NFE) AF: 0.873 AC: 945458 AN: 1083344

Other (OTH) AF: 0.863 AC: 50329 AN: 58318

GnomAD4 genome AF: 0.837 AC: 127451 AN: 152210 Hom.: 53503 Cov.: 33 AF XY: 0.835 AC XY: 62109 AN XY: 74416

African (AFR) AF: 0.792 AC: 32915 AN: 41544

American (AMR) AF: 0.785 AC: 12012 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3163 AN: 3472

East Asian (EAS) AF: 0.770 AC: 3972 AN: 5160

South Asian (SAS) AF: 0.821 AC: 3952 AN: 4816

European-Finnish (FIN) AF: 0.870 AC: 9217 AN: 10600

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.872 AC: 59324 AN: 68002

Other (OTH) AF: 0.867 AC: 1829 AN: 2110

Alfa AF: 0.861 Hom.: 132379

Bravo AF: 0.831

TwinsUK AF: 0.863 AC: 3199

ALSPAC AF: 0.874 AC: 3370

ESP6500AA AF: 0.816 AC: 3123

ESP6500EA AF: 0.885 AC: 7215

ExAC AF: 0.806 AC: 86496

Asia WGS AF: 0.784 AC: 2730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.057
DANN	Benign	0.38
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.76
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.11
ClinPred		0.0022	T
GERP RS		-4.9
Varity_R		0.018
gMVP		0.083
Mutation Taster		=100/0	polymorphism (auto)

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: rs11246212; hg19: chr11-610277; COSMIC: COSV52760026; COSMIC: COSV52760026;