20-62064849-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_003185.4(TAF4):c.962G>A(p.Gly321Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 958,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

TAF4
NM_003185.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0270

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1682696).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000415 (34/818442) while in subpopulation SAS AF= 0.000546 (9/16470). AF 95% confidence interval is 0.000284. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 20. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF4	NM_003185.4 link	c.962G>A	p.Gly321Asp	missense_variant	Exon 1 of 15	ENST00000252996.9	NP_003176.2	O00268
TAF4	XM_047440429.1 link	c.-155G>A		5_prime_UTR_variant	Exon 2 of 16		XP_047296385.1
MIR3195	NR_130463.1 link	n.48C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR3195	unassigned_transcript_3472	n.*21C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF4	ENST00000252996.9 link	c.962G>A	p.Gly321Asp	missense_variant	Exon 1 of 15	1	NM_003185.4	ENSP00000252996.3		O00268
MIR3195	ENST00000585001.1 link	n.48C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

140496

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000300

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000158

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000415

AC:

AN:

818442

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

378094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000546

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000334

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000356

AC:

AN:

140496

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

68166

show subpopulations

Gnomad4 AFR

AF:

0.0000508

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000300

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000218

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000158

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962G>A (p.G321D) alteration is located in exon 1 (coding exon 1) of the TAF4 gene. This alteration results from a G to A substitution at nucleotide position 962, causing the glycine (G) at amino acid position 321 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.073

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.23

M_CAP

Benign

0.037

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.050

REVEL

Benign

0.053

Sift

Uncertain

0.0080

Sift4G

Benign

0.63

Polyphen

0.87

Vest4

0.30

MutPred

0.21

Loss of catalytic residue at P317 (P = 0.1417);

MVP

0.093

MPC

0.89

ClinPred

0.21

GERP RS

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.099

gMVP

0.31

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