2-9849441-T-TA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_005680.3(TAF1B):c.197dup(p.Asn66LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0501 in 1,026,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.058 (0 hom.)
• Consequence: TAF1B NM_005680.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

Genes affected

TAF1B (HGNC:11533): (TATA-box binding protein associated factor, RNA polymerase I subunit B) Initiation of transcription by RNA polymerase I requires the formation of a complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs) specific for RNA polymerase I. This complex, known as SL1, binds to the core promoter of ribosomal RNA genes to position the polymerase properly and acts as a channel for regulatory signals. This gene encodes one of the SL1-specific TAFs. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF1B	NM_005680.3	c.197dup	p.Asn66LysfsTer4	frameshift_variant	3/15	ENST00000263663.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF1B	ENST00000263663.10	c.197dup	p.Asn66LysfsTer4	frameshift_variant	3/15	1	NM_005680.3	P1

Frequencies

GnomAD3 genomes AF: 0.000227 AC: 33 AN: 145660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000432

Gnomad FIN AF: 0.000439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000258

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0583 AC: 51348 AN: 880286 Hom.: 0 Cov.: 28 AF XY: 0.0590 AC XY: 25576 AN XY: 433588

Gnomad4 AFR exome AF: 0.0613

Gnomad4 AMR exome AF: 0.0640

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.0615

Gnomad4 SAS exome AF: 0.0809

Gnomad4 FIN exome AF: 0.0536

Gnomad4 NFE exome AF: 0.0563

Gnomad4 OTH exome AF: 0.0615

GnomAD4 genome AF: 0.000226 AC: 33 AN: 145722 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 21 AN XY: 70872

Gnomad4 AFR AF: 0.000150

Gnomad4 AMR AF: 0.000206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.000434

Gnomad4 FIN AF: 0.000439

Gnomad4 NFE AF: 0.000258

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Orofacial cleft 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Grupo de Genetica Humana, Facultad de Medicina - Universidad de La Sabana

Nov 22, 2022

VUS producing a null variant (frameshift) in the TAF1B gene, which encodes one of the proteins in the assembly of the RNA polymerase I preinitiation complex. Although no association has been proposed for this variant with orofacial cleft, it is predicted to produce Loss of Function, which is a known mechanism of disease for this gene and is located in a functional domain (“B-reader”) of the encoded protein. Other variants in TAF1B have achieved genome-wide significance for nonsyndromic orofacial clefts in a GWAS study with more than 7,000 patients with non-syndromic orofacial cleft. -

Computational scores

Source: dbNSFP v4.3

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: rs528368939; hg19: chr2-9989570;