1-109066217-T-C

Variant names:

• chr1-109066217-T-C
• rs773661572
• NM_005645.4:c.122A>G

Variant summary

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

The NM_005645.4(TAF13):​c.122A>G​(p.Tyr41Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TAF13 NM_005645.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

Genes affected

TAF13 (HGNC:11546): (TATA-box binding protein associated factor 13) 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 small subunit associated with a subset of TFIID complexes. This subunit interacts with TBP and with two other small subunits of TFIID, TAF10 and TAF11. There is a pseudogene located on chromosome 6. [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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF13	NM_005645.4	c.122A>G	p.Tyr41Cys	missense_variant	Exon 3 of 4	ENST00000338366.6	NP_005636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF13	ENST00000338366.6	c.122A>G	p.Tyr41Cys	missense_variant	Exon 3 of 4	1	NM_005645.4	ENSP00000355051.4
TAF13	ENST00000692048.1	c.122A>G	p.Tyr41Cys	missense_variant	Exon 3 of 5			ENSP00000508876.1
TAF13	ENST00000461096.7	c.8A>G	p.Tyr3Cys	missense_variant	Exon 3 of 4	5		ENSP00000433883.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 245034 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456356 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000233

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 60 Uncertain:1

Jun 19, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		Gain of catalytic residue at M39 (P = 0.0416);
MVP		0.66
MPC		2.3
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.87
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs773661572; hg19: chr1-109608839;