7-99450355-T-C

Variant names:

• chr7-99450355-T-C
• rs883403
• NM_006693.4:c.387T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_006693.4(CPSF4):​c.387T>C​(p.Arg129Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,266 control chromosomes in the GnomAD database, including 53,480 homozygotes. 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: 𝑓 0.36 (15705 hom., cov: 33)
  • Exomes 𝑓: 0.19 (37775 hom.)
• Consequence: CPSF4 NM_006693.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF4	NM_006693.4	c.387T>C	p.Arg129Arg	synonymous_variant	Exon 4 of 8	ENST00000292476.10	NP_006684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF4	ENST00000292476.10	c.387T>C	p.Arg129Arg	synonymous_variant	Exon 4 of 8	1	NM_006693.4	ENSP00000292476.5
ATP5MF-PTCD1	ENST00000413834.5	c.121+9731A>G		intron_variant	Intron 2 of 8	2		ENSP00000400168.1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54982 AN: 151910 Hom.: 15658 Cov.: 33

Gnomad AFR AF: 0.792

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.331

GnomAD3 exomes AF: 0.262 AC: 65544 AN: 250558 Hom.: 12189 AF XY: 0.252 AC XY: 34124 AN XY: 135562

Gnomad AFR exome AF: 0.806

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.334

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.194 AC: 283923 AN: 1460238 Hom.: 37775 Cov.: 31 AF XY: 0.196 AC XY: 142604 AN XY: 726464

Gnomad4 AFR exome AF: 0.819

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.362 AC: 55090 AN: 152028 Hom.: 15705 Cov.: 33 AF XY: 0.365 AC XY: 27125 AN XY: 74340

Gnomad4 AFR AF: 0.792

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.336

Alfa AF: 0.184 Hom.: 5142

Bravo AF: 0.385

Asia WGS AF: 0.409 AC: 1423 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.47
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs883403; hg19: chr7-99047978; COSMIC: COSV52856881; COSMIC: COSV52856881;