20-62006590-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003185.4(TAF4):c.2143A>G(p.Ser715Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,597,540 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: TAF4 NM_003185.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045203567).
• BP6: Variant 20-62006590-T-C is Benign according to our data. Variant chr20-62006590-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2672884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 319 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF4	NM_003185.4	c.2143A>G	p.Ser715Gly	missense_variant	7/15	ENST00000252996.9
TAF4	XM_047440429.1	c.1027A>G	p.Ser343Gly	missense_variant	8/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF4	ENST00000252996.9	c.2143A>G	p.Ser715Gly	missense_variant	7/15	1	NM_003185.4	P1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 151884 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00239 AC: 538 AN: 225330 Hom.: 2 AF XY: 0.00235 AC XY: 290 AN XY: 123304

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00180 AC: 2604 AN: 1445538 Hom.: 16 Cov.: 30 AF XY: 0.00176 AC XY: 1266 AN XY: 718544

Gnomad4 AFR exome AF: 0.0000915

Gnomad4 AMR exome AF: 0.000161

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00210 AC: 319 AN: 152002 Hom.: 4 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74282

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.000818 AC: 7

ExAC AF: 0.00221 AC: 265

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

TAF4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.077
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.52	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.82	N;.
REVEL	Benign	0.023
Sift	Benign	0.060	T;.
Sift4G	Benign	0.24	T;T
Polyphen		0.0070	B;.
Vest4		0.30
MVP		0.37
MPC		0.63
ClinPred		0.018	T
GERP RS		3.1
Varity_R		0.052
gMVP		0.25

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

Other links and lift over

dbSNP: rs142826042; hg19: chr20-60581646;