X-71377717-C-CAGG

Variant names:

• chrX-71377717-C-CAGG
• rs773753966
• NM_004606.5:c.833_835dupAGG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_004606.5(TAF1):​c.833_835dupAGG​(p.Glu278dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00104 in 111,479 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (1 hom. 542 hem.)
  • Failed GnomAD Quality Control
• Consequence: TAF1 NM_004606.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.46
• 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: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004606.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-71377717-C-CAGG is Benign according to our data. Variant chrX-71377717-C-CAGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00104 (116/111479) while in subpopulation NFE AF = 0.00186 (99/53126). AF 95% confidence interval is 0.00157. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 26 XL,Unknown gene

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.833_835dupAGG	p.Glu278dup	disruptive_inframe_insertion	Exon 6 of 38	NP_004597.3
	TAF1	NM_001286074.2		c.833_835dupAGG	p.Glu278dup	disruptive_inframe_insertion	Exon 6 of 39	NP_001273003.2
	TAF1	NM_001440852.1		c.833_835dupAGG	p.Glu278dup	disruptive_inframe_insertion	Exon 6 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.833_835dupAGG	p.Glu278dup	disruptive_inframe_insertion	Exon 6 of 38	ENSP00000406549.2
	TAF1	ENST00000373790.9	TSL:1	c.770_772dupAGG	p.Glu257dup	disruptive_inframe_insertion	Exon 6 of 38	ENSP00000362895.5
	TAF1	ENST00000683782.1		c.833_835dupAGG	p.Glu278dup	disruptive_inframe_insertion	Exon 6 of 39	ENSP00000506996.1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 116 AN: 111426 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00186

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000676 AC: 124 AN: 183388 AF XY: 0.000722

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000663

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00156 AC: 1717 AN: 1098207 Hom.: 1 Cov.: 31 AF XY: 0.00149 AC XY: 542 AN XY: 363567

African (AFR) AF: 0.000303 AC: 8 AN: 26400

American (AMR) AF: 0.000284 AC: 10 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00193 AC: 1623 AN: 842126

Other (OTH) AF: 0.00163 AC: 75 AN: 46094

GnomAD4 genome AF: 0.00104 AC: 116 AN: 111479 Hom.: 0 Cov.: 22 AF XY: 0.000772 AC XY: 26 AN XY: 33657

African (AFR) AF: 0.000260 AC: 8 AN: 30734

American (AMR) AF: 0.000675 AC: 7 AN: 10368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2631

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.00186 AC: 99 AN: 53126

Other (OTH) AF: 0.00132 AC: 2 AN: 1511

Alfa AF: 0.00131 Hom.: 10

Bravo AF: 0.000960

EpiCase AF: 0.00180

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	TAF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=73/27	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773753966; hg19: chrX-70597567;