X-78138051-C-T

Variant names:

• chrX-78138051-C-T
• rs149136745
• NM_015975.5:c.181G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015975.5(TAF9B):​c.181G>A​(p.Ala61Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,206,854 control chromosomes in the GnomAD database, including 1 homozygotes. There are 55 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (1 hom. 51 hem.)
• Consequence: TAF9B NM_015975.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11825657).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF9B	NM_015975.5	c.181G>A	p.Ala61Thr	missense_variant	Exon 3 of 7	ENST00000341864.6	NP_057059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF9B	ENST00000341864.6	c.181G>A	p.Ala61Thr	missense_variant	Exon 3 of 7	1	NM_015975.5	ENSP00000339917.5
TAF9B	ENST00000480681.1	n.192G>A		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 112403 Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4 AN XY: 34557

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

Gnomad ASJ AF: 0.00453

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000345 AC: 62 AN: 179605 Hom.: 0 AF XY: 0.000264 AC XY: 17 AN XY: 64373

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000751

Gnomad ASJ exome AF: 0.00698

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000865

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000154 AC: 169 AN: 1094451 Hom.: 1 Cov.: 29 AF XY: 0.000141 AC XY: 51 AN XY: 360539

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000575

Gnomad4 ASJ exome AF: 0.00673

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000214

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000125 AC: 14 AN: 112403 Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4 AN XY: 34557

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000940

Gnomad4 ASJ AF: 0.00453

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000204 Hom.: 6

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>A (p.A61T) alteration is located in exon 3 (coding exon 3) of the TAF9B gene. This alteration results from a G to A substitution at nucleotide position 181, causing the alanine (A) at amino acid position 61 to be replaced by a threonine (T). 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	0.88
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.75
MPC		0.25
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.71
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs149136745; hg19: chrX-77393548;