rs12805435

Variant names:

• chr11-612355-T-A
• rs12805435
• NM_001286581.2:c.*578T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-612355-T-A
• chr11-612355-T-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.*578T>A variant causes a downstream gene 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHRF1 NM_001286581.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 19 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]

IRF7 (HGNC:6122): (interferon regulatory factor 7) This gene encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. It has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including interferon beta chain genes. Inducible expression of IRF7 is largely restricted to lymphoid tissue. The encoded protein plays an important role in the innate immune response against DNA and RNA viruses. [provided by RefSeq, Jul 2021]

IRF7 Gene-Disease associations (from GenCC):

• immunodeficiency 39

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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 (BayesDel_noAF=-0.89).

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.*578T>A		downstream_gene	N/A	NP_001273510.1	Q9P1Y6-1
	IRF7	NM_001572.5	MANE Select	c.*290A>T		downstream_gene	N/A	NP_001563.2
	PHRF1	NM_020901.4		c.*578T>A		downstream_gene	N/A	NP_065952.2	Q9P1Y6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHRF1	ENST00000264555.10	TSL:1 MANE Select	c.*578T>A		downstream_gene	N/A	ENSP00000264555.5	Q9P1Y6-1
	IRF7	ENST00000525445.6	TSL:5 MANE Select	c.*290A>T		downstream_gene	N/A	ENSP00000434009.2	Q92985-1
	IRF7	ENST00000397566.5	TSL:1	c.*290A>T		downstream_gene	N/A	ENSP00000380697.1	Q92985-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000549 AC: 2 AN: 364588 Hom.: 0 AF XY: 0.00000527 AC XY: 1 AN XY: 189730

⚠️ 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: 11030

American (AMR) AF: 0.00 AC: 0 AN: 14496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11716

East Asian (EAS) AF: 0.00 AC: 0 AN: 26494

South Asian (SAS) AF: 0.00 AC: 0 AN: 33856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1662

European-Non Finnish (NFE) AF: 0.00000909 AC: 2 AN: 220066

Other (OTH) AF: 0.00 AC: 0 AN: 21750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 7175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.70
PhyloP100		-0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12805435; hg19: chr11-612355;