chr1-222563237-C-T

Variant names:

• chr1-222563237-C-T
• rs765321518
• NM_005681.4:c.1021G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005681.4(TAF1A):​c.1021G>A​(p.Gly341Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,612,710 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: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TAF1A NM_005681.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.60
• Publications: 4 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• BS2: High AC in GnomAd4 at 6 AD gene.

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.1021G>A	p.Gly341Arg	missense	Exon 9 of 11	NP_005672.1	Q15573-1
	TAF1A	NM_001201536.1		c.1021G>A	p.Gly341Arg	missense	Exon 9 of 12	NP_001188465.1	A8K4K5
	TAF1A	NM_139352.2		c.679G>A	p.Gly227Arg	missense	Exon 8 of 11	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.1021G>A	p.Gly341Arg	missense	Exon 9 of 11	ENSP00000327072.6	Q15573-1
	TAF1A	ENST00000972077.1		c.1156G>A	p.Gly386Arg	missense	Exon 10 of 12	ENSP00000642136.1
	TAF1A	ENST00000350027.8	TSL:2	c.1021G>A	p.Gly341Arg	missense	Exon 9 of 12	ENSP00000339976.4	Q15573-1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152036 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250252 AF XY: 0.0000222

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460674 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726700

African (AFR) AF: 0.0000299 AC: 1 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39590

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86160

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111428

Other (OTH) AF: 0.0000497 AC: 3 AN: 60328

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152036 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.0000242 AC: 1 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy, familial restrictive, 6 (1)
-	1	-	not provided (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.47		Gain of MoRF binding (P = 0.012)
MVP		0.75
MPC		0.99
ClinPred		0.61	D
GERP RS		6.0
Varity_R		0.33
gMVP		0.53
Mutation Taster		=7/93	disease causing

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: rs765321518; hg19: chr1-222736579;