rs864321627

Positions:

• chrX-71401691-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_004606.5(TAF1):​c.3950T>C​(p.Ile1317Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TAF1 NM_004606.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67

Genes affected

TAF1 (HGNC:11535): (TATA-box binding protein associated factor 1) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is the basal transcription factor 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 the largest subunit of TFIID. This subunit binds to core promoter sequences encompassing the transcription start site. It also binds to activators and other transcriptional regulators, and these interactions affect the rate of transcription initiation. This subunit contains two independent protein kinase domains at the N- and C-terminals, but also possesses acetyltransferase activity and can act as a ubiquitin-activating/conjugating enzyme. Mutations in this gene result in Dystonia 3, torsion, X-linked, a dystonia-parkinsonism disorder. Alternative splicing of this gene results in multiple transcript variants. This gene is part of a complex transcription unit (TAF1/DYT3), wherein some transcript variants share exons with TAF1 as well as additional downstream DYT3 exons. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TAF1. . Gene score misZ 5.486 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome, X-linked dystonia-parkinsonism, intellectual disability, X-linked, syndromic 33.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant X-71401691-T-C is Pathogenic according to our data. Variant chrX-71401691-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 219114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71401691-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF1	NM_004606.5	c.3950T>C	p.Ile1317Thr	missense_variant	25/38	ENST00000423759.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF1	ENST00000423759.6	c.3950T>C	p.Ile1317Thr	missense_variant	25/38	5	NM_004606.5	A2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked, syndromic 33 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics Institute, Tel Aviv Sourasky Medical Center	May 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Medicine, Institute for Basic Research in Developmental Disabilities	Aug 08, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.98, 1.0	.;D;D
Vest4		0.68
MutPred		0.43		.;Loss of stability (P = 0.0016);.;
MVP		0.93
MPC		3.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.90

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: rs864321627; hg19: chrX-70621541; COSMIC: COSV52111070; COSMIC: COSV52111070;