X-78137868-C-A

Variant names:

• chrX-78137868-C-A
• rs372088655
• NM_015975.5:c.286G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015975.5(TAF9B):​c.286G>T​(p.Ala96Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,089,728 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: TAF9B NM_015975.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

Genes affected

TAF9B (HGNC:17306): (TATA-box binding protein associated factor 9b) 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 a protein that is similar to one of the small subunits of TFIID, TBP-associated factor 9, and is also a subunit of TFIID. TAF9 and TAF9b share some functions but also have distinct roles in the transcriptional regulatory process. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015975.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF9B	NM_015975.5	MANE Select	c.286G>T	p.Ala96Ser	missense	Exon 4 of 7	NP_057059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF9B	ENST00000341864.6	TSL:1 MANE Select	c.286G>T	p.Ala96Ser	missense	Exon 4 of 7	ENSP00000339917.5	Q9HBM6
	TAF9B	ENST00000888659.1		c.286G>T	p.Ala96Ser	missense	Exon 4 of 6	ENSP00000558718.1
	TAF9B	ENST00000888658.1		c.270+94G>T		intron	N/A	ENSP00000558717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1089728 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 1 AN XY: 357446

African (AFR) AF: 0.00 AC: 0 AN: 25809

American (AMR) AF: 0.00 AC: 0 AN: 32961

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18973

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3991

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839842

Other (OTH) AF: 0.00 AC: 0 AN: 45685

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.92		Gain of phosphorylation at A96 (P = 0.0845)
MVP		0.93
MPC		0.46
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.62
gMVP		0.54
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs372088655; hg19: chrX-77393365;