chr7-99450781-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006693.4(CPSF4):c.483G>A(p.Ser161Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,090 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 33)

Exomes 𝑓: 0.015 ( 197 hom. )

Consequence

CPSF4
NM_006693.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.15

Variant links:

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]

CPSF4 links:

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]

ATP5MF-PTCD1 links:

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]

PTCD1 links:

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]

ATP5MF links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 7-99450781-G-A is Benign according to our data. Variant chr7-99450781-G-A is described in ClinVar as [Benign]. Clinvar id is 769333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1598/152338) while in subpopulation NFE AF= 0.0167 (1134/68032). AF 95% confidence interval is 0.0159. There are 14 homozygotes in gnomad4. There are 729 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF4	NM_006693.4 link	c.483G>A	p.Ser161Ser	synonymous_variant	Exon 5 of 8	ENST00000292476.10	NP_006684.1	O95639-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF4	ENST00000292476.10 link	c.483G>A	p.Ser161Ser	synonymous_variant	Exon 5 of 8	1	NM_006693.4	ENSP00000292476.5		O95639-1
ATP5MF-PTCD1	ENST00000413834.5 link	c.121+9305C>T		intron_variant	Intron 2 of 8	2		ENSP00000400168.1		G3V325

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1603

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0101

AC:

2528

AN:

251202

Hom.:

AF XY:

0.00993

AC XY:

1348

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00622

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00336

Gnomad FIN exome

AF:

0.00630

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0149

AC:

21728

AN:

1460752

Hom.:

197

Cov.:

AF XY:

0.0144

AC XY:

10497

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.00693

Gnomad4 ASJ exome

AF:

0.00555

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00392

Gnomad4 FIN exome

AF:

0.00548

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0105

AC:

1598

AN:

152338

Hom.:

Cov.:

AF XY:

0.00979

AC XY:

729

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00356

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0194

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.26

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over