NM_006693.4:c.483G>C

Variant names:

• chr7-99450781-G-C
• rs35303224
• NM_006693.4:c.483G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_006693.4(CPSF4):​c.483G>C​(p.Ser161Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S161S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CPSF4 NM_006693.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 0 publications found

Genes affected

CPSF4 (HGNC:2327): (cleavage and polyadenylation specific factor 4) Inhibition of the nuclear export of poly(A)-containing mRNAs caused by the influenza A virus NS1 protein requires its effector domain. The NS1 effector domain functionally interacts with the cellular 30 kDa subunit of cleavage and polyadenylation specific factor 4, an essential component of the 3' end processing machinery of cellular pre-mRNAs. In influenza virus-infected cells, the NS1 protein is physically associated with cleavage and polyadenylation specific factor 4, 30kD subunit. Binding of the NS1 protein to the 30 kDa protein in vitro prevents CPSF binding to the RNA substrate and inhibits 3' end cleavage and polyadenylation of host pre-mRNAs. Thus the NS1 protein selectively inhibits the nuclear export of cellular, and not viral, mRNAs. Multiple alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ATP5MF-PTCD1 (HGNC:38844): (ATP5MF-PTCD1 readthrough) This locus represents naturally occurring read-through transcription between the ATP5J2 (ATP synthase, H+ transporting, mitochondrial Fo complex, subunit F2) and PTCD1 (pentatricopeptide repeat domain 1) genes on chromosome 7. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

PTCD1 (HGNC:22198): (pentatricopeptide repeat domain 1) This gene encodes a mitochondrial protein that binds leucine tRNAs and other mitochondrial RNAs and plays a role in the regulation of translation. Increased expression of this gene results in decreased mitochondrial leucine tRNA levels. Naturally occurring read-through transcription exists between upstream ATP5J2 (ATP synthase, H+ transporting, mitochondrial Fo complex, subunit F2) and this gene. [provided by RefSeq, Aug 2015]

ATP5MF (HGNC:848): (ATP synthase membrane subunit f) Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The catalytic portion of mitochondrial ATP synthase consists of five different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and single representatives of the gamma, delta, and epsilon subunits. The proton channel likely has nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the f subunit of the Fo complex. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. This gene has multiple pseudogenes. Naturally occurring read-through transcription also exists between this gene and the downstream pentatricopeptide repeat domain 1 (PTCD1) gene. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.092).
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006693.4. 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
	CPSF4	NM_006693.4	MANE Select	c.483G>C	p.Ser161Ser	synonymous	Exon 5 of 8	NP_006684.1	O95639-1
	CPSF4	NM_001081559.3		c.483G>C	p.Ser161Ser	synonymous	Exon 5 of 8	NP_001075028.1	O95639-2
	CPSF4	NM_001318160.2		c.483G>C	p.Ser161Ser	synonymous	Exon 5 of 8	NP_001305089.1	O95639-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF4	ENST00000292476.10	TSL:1 MANE Select	c.483G>C	p.Ser161Ser	synonymous	Exon 5 of 8	ENSP00000292476.5	O95639-1
	CPSF4	ENST00000436336.6	TSL:1	c.483G>C	p.Ser161Ser	synonymous	Exon 5 of 8	ENSP00000395311.2	O95639-2
	ATP5MF-PTCD1	ENST00000413834.5	TSL:2	c.121+9305C>G		intron	N/A	ENSP00000400168.1	G3V325

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460898 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726720

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111462

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.052
DANN	Benign	0.70
PhyloP100		-1.1
PromoterAI		0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35303224; hg19: chr7-99048404;