5-69365395-A-C

Position:

• chr5-69365395-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003187.5(TAF9):​c.343T>G​(p.Leu115Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TAF9 NM_003187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

Genes affected

TAF9 (HGNC:11542): (TATA-box binding protein associated factor 9) 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 one of the smaller subunits of TFIID that binds to the basal transcription factor GTF2B as well as to several transcriptional activators such as p53 and VP16. In human, TAF9 and AK6 (GeneID: 102157402) are two distinct genes that share 5' exons. A similar but distinct gene (TAF9L) has been found on the X chromosome and a pseudogene has been identified on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

AK6 (HGNC:49151): (adenylate kinase 6) This gene encodes a protein that belongs to the adenylate kinase family of enzymes. The protein has a nuclear localization and contains Walker A (P-loop) and Walker B motifs and a metal-coordinating residue. The protein may be involved in regulation of Cajal body formation. In human, AK6 and TAF9 (GeneID: 6880) are two distinct genes that share 5' exons. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF9	NM_003187.5	c.343T>G	p.Leu115Val	missense_variant	3/3	ENST00000217893.10
AK6	NM_016283.5	c.121+1108T>G		intron_variant		ENST00000380822.9
TAF9	NM_001015892.2	c.343T>G	p.Leu115Val	missense_variant	3/3
AK6	NM_001015891.2	c.112+1108T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF9	ENST00000217893.10	c.343T>G	p.Leu115Val	missense_variant	3/3	1	NM_003187.5	P1
AK6	ENST00000380822.9	c.121+1108T>G		intron_variant		1	NM_016283.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.343T>G (p.L115V) alteration is located in exon 3 (coding exon 1) of the TAF9 gene. This alteration results from a T to G substitution at nucleotide position 343, causing the leucine (L) at amino acid position 115 to be replaced by a valine (V). 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	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D;T;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;D
Polyphen		0.99	D;D;D;.;.;.;.
Vest4		0.86
MutPred		0.78		Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);Loss of catalytic residue at L115 (P = 0.0082);
MVP		0.86
MPC		0.98
ClinPred		0.97	D
GERP RS		0.32
Varity_R		0.68
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-68661222;