chr1-222584139-C-T

Variant names:

• chr1-222584139-C-T
• rs956228152
• NM_005681.4:c.280G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005681.4(TAF1A):​c.280G>A​(p.Ala94Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A94V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TAF1A NM_005681.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350
• Publications: 0 publications found

Genes affected

TAF1A (HGNC:11532): (TATA-box binding protein associated factor, RNA polymerase I subunit A) This gene encodes a subunit of the RNA polymerase I complex, Selectivity Factor I (SLI). The encoded protein is a TATA box-binding protein-associated factor that plays a role in the assembly of the RNA polymerase I preinitiation complex. Alternate splicing results in multiple transcript variants encoding multiple isoforms.[provided by RefSeq, Jan 2011]

TAF1A Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037549973).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005681.4. 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
	TAF1A	NM_005681.4	MANE Select	c.280G>A	p.Ala94Thr	missense	Exon 3 of 11	NP_005672.1	Q15573-1
	TAF1A	NM_001201536.1		c.280G>A	p.Ala94Thr	missense	Exon 3 of 12	NP_001188465.1	A8K4K5
	TAF1A	NM_139352.2		c.-51-4267G>A		intron	N/A	NP_647603.1	Q15573-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1A	ENST00000352967.9	TSL:1 MANE Select	c.280G>A	p.Ala94Thr	missense	Exon 3 of 11	ENSP00000327072.6	Q15573-1
	TAF1A	ENST00000972077.1		c.280G>A	p.Ala94Thr	missense	Exon 3 of 12	ENSP00000642136.1
	TAF1A	ENST00000350027.8	TSL:2	c.280G>A	p.Ala94Thr	missense	Exon 3 of 12	ENSP00000339976.4	Q15573-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456862 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 724686

⚠️ 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: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52710

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110674

Other (OTH) AF: 0.00 AC: 0 AN: 60232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.9
DANN	Benign	0.88
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.035
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.044
Sift	Benign	0.33	T
Sift4G	Benign	0.37	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.17		Gain of phosphorylation at A94 (P = 0.0373)
MVP		0.28
MPC		0.25
ClinPred		0.039	T
GERP RS		2.9
Varity_R		0.039
gMVP		0.12
Mutation Taster		=98/2	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: rs956228152; hg19: chr1-222757481;