Genetic Variant TAF4:p.Ala323Ala (chr20-62064842-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003185.4(TAF4):c.969G>T(p.Ala323Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 965,642 control chromosomes in the GnomAD database, including 21,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2048 hom., cov: 24)

Exomes 𝑓: 0.21 ( 19339 hom. )

Consequence

TAF4
NM_003185.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.307

Variant links:

Genes affected

TAF4 (HGNC:11537): (TATA-box binding protein associated factor 4) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the larger subunits of TFIID that has been shown to potentiate transcriptional activation by retinoic acid, thyroid hormone and vitamin D3 receptors. In addition, this subunit interacts with the transcription factor CREB, which has a glutamine-rich activation domain, and binds to other proteins containing glutamine-rich regions. Aberrant binding to this subunit by proteins with expanded polyglutamine regions has been suggested as one of the pathogenetic mechanisms underlying a group of neurodegenerative disorders referred to as polyglutamine diseases. [provided by RefSeq, Jul 2008]

TAF4 links:

MIR3195 (HGNC:38250): (microRNA 3195) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR3195 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=-0.46).

BP6

Variant 20-62064842-C-A is Benign according to our data. Variant chr20-62064842-C-A is described in ClinVar as [Benign]. Clinvar id is 1227169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.307 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF4	NM_003185.4 link	c.969G>T	p.Ala323Ala	synonymous_variant	Exon 1 of 15	ENST00000252996.9	NP_003176.2	O00268

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF4	ENST00000252996.9 link	c.969G>T	p.Ala323Ala	synonymous_variant	Exon 1 of 15	1	NM_003185.4	ENSP00000252996.3		O00268
MIR3195	ENST00000585001.1 link	n.41C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

21145

AN:

139890

Hom.:

2049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0444

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.0800

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.187

GnomAD3 exomes

AF:

0.361

AC:

AN:

Hom.:

AF XY:

0.417

AC XY:

AN XY:

show subpopulations

Gnomad NFE exome

AF:

0.361

GnomAD4 exome

AF:

0.213

AC:

175952

AN:

825760

Hom.:

19339

Cov.:

AF XY:

0.213

AC XY:

81407

AN XY:

381568

show subpopulations

Gnomad4 AFR exome

AF:

0.0281

Gnomad4 AMR exome

AF:

0.185

Gnomad4 ASJ exome

AF:

0.226

Gnomad4 EAS exome

AF:

0.0837

Gnomad4 SAS exome

AF:

0.171

Gnomad4 FIN exome

AF:

0.150

Gnomad4 NFE exome

AF:

0.219

Gnomad4 OTH exome

AF:

0.197

GnomAD4 genome

AF:

0.151

AC:

21127

AN:

139882

Hom.:

2048

Cov.:

AF XY:

0.147

AC XY:

9984

AN XY:

67896

show subpopulations

Gnomad4 AFR

AF:

0.0443

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.223

Gnomad4 EAS

AF:

0.0800

Gnomad4 SAS

AF:

0.158

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.213

Gnomad4 OTH

AF:

0.185

Alfa

AF:

0.170

Hom.:

389

Bravo

AF:

0.148

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 02, 2019

GeneDx

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

-0.46

CADD

Benign

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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