X-71366375-A-T

Variant names:

• chrX-71366375-A-T
• NM_004606.5:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Supporting PM2 PP5

The NM_004606.5(TAF1):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,association (no stars).

• Frequency: Genomes: not found (cov: 20)
• Consequence: TAF1 NM_004606.5 initiator_codon
• Clinical Significance: Likely pathogenic; association no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.36

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 108 codons. Genomic position: 71368140. Lost 0.057 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71366375-A-T is Pathogenic according to our data. Variant chrX-71366375-A-T is described in ClinVar as [Likely_pathogenic, association]. Clinvar id is 1184816.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1	NM_004606.5	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 38	ENST00000423759.6	NP_004597.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1	ENST00000423759.6	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 38	5	NM_004606.5	ENSP00000406549.2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 20

ClinVar

Significance: Likely pathogenic; association

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked, syndromic 33 Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Heart, malformation of Other:1

Jun 13, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.11	.;T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.17, 0.26	.;B;B
Vest4		0.49
MutPred		0.31		Loss of catalytic residue at M21 (P = 0.0125);Loss of catalytic residue at M21 (P = 0.0125);Loss of catalytic residue at M21 (P = 0.0125);
MVP		0.70
MPC		0.70
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70586225;