X-78139567-A-T

Variant names:

• chrX-78139567-A-T
• NM_015975.5:c.45T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015975.5(TAF9B):​c.45T>A​(p.Asp15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,097,877 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: TAF9B NM_015975.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF9B	NM_015975.5	c.45T>A	p.Asp15Glu	missense_variant	Exon 1 of 7	ENST00000341864.6	NP_057059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF9B	ENST00000341864.6	c.45T>A	p.Asp15Glu	missense_variant	Exon 1 of 7	1	NM_015975.5	ENSP00000339917.5
TAF9B	ENST00000480681.1	n.56T>A		non_coding_transcript_exon_variant	Exon 1 of 6	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097877 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363293

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.45T>A (p.D15E) alteration is located in exon 1 (coding exon 1) of the TAF9B gene. This alteration results from a T to A substitution at nucleotide position 45, causing the aspartic acid (D) at amino acid position 15 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.85
MutPred		0.90		Gain of disorder (P = 0.1048);
MVP		0.75
MPC		0.50
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.77
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-77395064;