X-71389657-G-A

Variant names:

• chrX-71389657-G-A
• rs1555971253
• NM_004606.5:c.2773G>A

Variant summary

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

The NM_004606.5(TAF1):​c.2773G>A​(p.Asp925Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D925D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: TAF1 NM_004606.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.46
• Publications: 0 publications found

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]

TAF1 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked, syndromic 33

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• X-linked dystonia-parkinsonism

  Inheritance: XL, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

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_004606.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	NM_004606.5	MANE Select	c.2773G>A	p.Asp925Asn	missense	Exon 18 of 38	NP_004597.3
	TAF1	NM_001286074.2		c.2773G>A	p.Asp925Asn	missense	Exon 18 of 39	NP_001273003.2
	TAF1	NM_001440852.1		c.2773G>A	p.Asp925Asn	missense	Exon 18 of 39	NP_001427781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000423759.6	TSL:5 MANE Select	c.2773G>A	p.Asp925Asn	missense	Exon 18 of 38	ENSP00000406549.2
	TAF1	ENST00000373790.9	TSL:1	c.2710G>A	p.Asp904Asn	missense	Exon 18 of 38	ENSP00000362895.5
	TAF1	ENST00000683782.1		c.2773G>A	p.Asp925Asn	missense	Exon 18 of 39	ENSP00000506996.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 24, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 23, 2019

Genome Medicine, Institute for Basic Research in Developmental Disabilities

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.29
Sift	Benign	0.072	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.30		Gain of MoRF binding (P = 0.0981)
MVP		0.80
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.87
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs1555971253; hg19: chrX-70609507;