11-610277-T-C

Position:

• chr11-610277-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHRF1	NM_001286581.2	c.4346T>C	p.Val1449Ala	missense_variant	15/18	ENST00000264555.10	NP_001273510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHRF1	ENST00000264555.10	c.4346T>C	p.Val1449Ala	missense_variant	15/18	1	NM_001286581.2	ENSP00000264555	P5

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

GnomAD3 exomes AF: 0.838 AC: 138858 AN: 165764 Hom.: 58416 AF XY: 0.842 AC XY: 74737 AN XY: 88784

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 SAS exome AF: 0.837

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

Gnomad4 AFR exome AF: 0.781

Gnomad4 AMR exome AF: 0.766

Gnomad4 ASJ exome AF: 0.910

Gnomad4 EAS exome AF: 0.792

Gnomad4 SAS exome AF: 0.836

Gnomad4 FIN exome AF: 0.861

Gnomad4 NFE exome AF: 0.873

Gnomad4 OTH exome AF: 0.863

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

Gnomad4 AFR AF: 0.792

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.911

Gnomad4 EAS AF: 0.770

Gnomad4 SAS AF: 0.821

Gnomad4 FIN AF: 0.870

Gnomad4 NFE AF: 0.872

Gnomad4 OTH AF: 0.867

Alfa AF: 0.869 Hom.: 87622

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 v4.3

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;.;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.22	T;T;T;T
MetaRNN	Benign	8.8e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.0	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.73	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.023
MPC		0.11
ClinPred		0.0022	T
GERP RS		-4.9
Varity_R		0.018
gMVP		0.083

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