chr20-62064838-C-A

Variant names:

• chr20-62064838-C-A
• rs1369654553
• NM_003185.4:c.973G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003185.4(TAF4):​c.973G>T​(p.Val325Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 971,172 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: TAF4 NM_003185.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

Genes affected

TAF4 (HGNC:11537): (TATA-box binding protein associated factor 4) 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 larger subunits of TFIID that has been shown to potentiate transcriptional activation by retinoic acid, thyroid hormone and vitamin D3 receptors. In addition, this subunit interacts with the transcription factor CREB, which has a glutamine-rich activation domain, and binds to other proteins containing glutamine-rich regions. Aberrant binding to this subunit by proteins with expanded polyglutamine regions has been suggested as one of the pathogenetic mechanisms underlying a group of neurodegenerative disorders referred to as polyglutamine diseases. [provided by RefSeq, Jul 2008]

MIR3195 (HGNC:38250): (microRNA 3195) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ENSG00000283078 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022556126).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00199 (282/141920) while in subpopulation AFR AF = 0.00686 (273/39788). AF 95% confidence interval is 0.00619. There are 0 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 282 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003185.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF4	NM_003185.4	MANE Select	c.973G>T	p.Val325Phe	missense	Exon 1 of 15	NP_003176.2	O00268
	MIR3195	NR_130463.1		n.37C>A		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF4	ENST00000252996.9	TSL:1 MANE Select	c.973G>T	p.Val325Phe	missense	Exon 1 of 15	ENSP00000252996.3	O00268
	MIR3195	ENST00000585001.1	TSL:6	n.37C>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000283078	ENST00000751839.1		n.111+317C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 280 AN: 141942 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000207 AC: 172 AN: 829252 Hom.: 2 Cov.: 22 AF XY: 0.000224 AC XY: 86 AN XY: 383156

African (AFR) AF: 0.00968 AC: 152 AN: 15708

American (AMR) AF: 0.00 AC: 0 AN: 1034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5158

East Asian (EAS) AF: 0.00 AC: 0 AN: 3624

South Asian (SAS) AF: 0.00 AC: 0 AN: 16808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1612

European-Non Finnish (NFE) AF: 0.0000119 AC: 9 AN: 757788

Other (OTH) AF: 0.000404 AC: 11 AN: 27202

GnomAD4 genome AF: 0.00199 AC: 282 AN: 141920 Hom.: 0 Cov.: 24 AF XY: 0.00197 AC XY: 136 AN XY: 68960

African (AFR) AF: 0.00686 AC: 273 AN: 39788

American (AMR) AF: 0.000620 AC: 9 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4722

South Asian (SAS) AF: 0.00 AC: 0 AN: 4614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64074

Other (OTH) AF: 0.00 AC: 0 AN: 1970

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.057
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		0.12	B
Vest4		0.29
MutPred		0.19		Loss of sheet (P = 0.1398)
MVP		0.068
MPC		0.91
ClinPred		0.26	T
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.30
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1369654553; hg19: chr20-60639894;