chr10-103368446-G-C

Variant names:

• chr10-103368446-G-C
• rs2093350749
• NM_006951.5:c.457G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006951.5(TAF5):​c.457G>C​(p.Ala153Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TAF5 NM_006951.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• Publications: 0 publications found

Genes affected

TAF5 (HGNC:11539): (TATA-box binding protein associated factor 5) 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 an integral subunit of TFIID associated with all transcriptionally competent forms of that complex. This subunit interacts strongly with two TFIID subunits that show similarity to histones H3 and H4, and it may participate in forming a nucleosome-like core in the TFIID complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21933708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF5	NM_006951.5	c.457G>C	p.Ala153Pro	missense_variant	Exon 1 of 11	ENST00000369839.4	NP_008882.2
TAF5	NM_139052.3	c.457G>C	p.Ala153Pro	missense_variant	Exon 1 of 10		NP_620640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF5	ENST00000369839.4	c.457G>C	p.Ala153Pro	missense_variant	Exon 1 of 11	1	NM_006951.5	ENSP00000358854.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429450 Hom.: 0 Cov.: 35 AF XY: 0.00000141 AC XY: 1 AN XY: 710302

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32650

American (AMR) AF: 0.00 AC: 0 AN: 42502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38832

South Asian (SAS) AF: 0.00 AC: 0 AN: 83880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4606

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105408

Other (OTH) AF: 0.00 AC: 0 AN: 59418

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457G>C (p.A153P) alteration is located in exon 1 (coding exon 1) of the TAF5 gene. This alteration results from a G to C substitution at nucleotide position 457, causing the alanine (A) at amino acid position 153 to be replaced by a proline (P). 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	Benign	0.11
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.048
Sift	Uncertain	0.021	D
Sift4G	Benign	0.31	T
Polyphen		0.98	D
Vest4		0.20
MutPred		0.14		Gain of glycosylation at A153 (P = 0.0462);
MVP		0.31
MPC		1.7
ClinPred		0.92	D
GERP RS		4.2
PromoterAI		-0.011	Neutral
Varity_R		0.41
gMVP		0.34
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs2093350749; hg19: chr10-105128203;