NM_003185.4:c.2608G>A

Variant names:

• chr20-62000600-C-T
• NM_003185.4:c.2608G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003185.4(TAF4):​c.2608G>A​(p.Glu870Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TAF4 NM_003185.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 73

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia

LOC105372704 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003185.4. 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
	TAF4	NM_003185.4	MANE Select	c.2608G>A	p.Glu870Lys	missense	Exon 10 of 15	NP_003176.2	O00268

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF4	ENST00000252996.9	TSL:1 MANE Select	c.2608G>A	p.Glu870Lys	missense	Exon 10 of 15	ENSP00000252996.3	O00268
	TAF4	ENST00000488539.1	TSL:5	c.613G>A	p.Glu205Lys	missense	Exon 5 of 5	ENSP00000476294.1	V9GY14
	TAF4	ENST00000436129.2	TSL:2	n.979G>A		non_coding_transcript_exon	Exon 6 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.93	P
Vest4		0.59
MutPred		0.61		Gain of catalytic residue at E870 (P = 0.0111)
MVP		0.44
MPC		1.6
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.60
Mutation Taster		=50/50

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

Other links and lift over

hg19: chr20-60575656;