1-222563237-C-T

Position:

chr1-222563237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000352967.9(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
ENST00000352967.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.60

Variant links:

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 links:

TAF1A (HGNC:):

TAF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAF1A	NM_005681.4 linkuse as main transcript	c.1021G>A	p.Gly341Arg	missense_variant	9/11	ENST00000352967.9	NP_005672.1	Q15573-1B4DS21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TAF1A	ENST00000352967.9 linkuse as main transcript	c.1021G>A	p.Gly341Arg	missense_variant	9/11	1	NM_005681.4	ENSP00000327072.6	Q15573-1
TAF1A	ENST00000350027.8 linkuse as main transcript	c.1021G>A	p.Gly341Arg	missense_variant	9/12	2		ENSP00000339976.4	Q15573-1
TAF1A	ENST00000366890.5 linkuse as main transcript	c.679G>A	p.Gly227Arg	missense_variant	8/11	2		ENSP00000355856.1	Q15573-2
TAF1A	ENST00000391883.2 linkuse as main transcript	c.*48G>A		downstream_gene_variant		5		ENSP00000375755.2	Q5JRA7

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250252

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135322

show subpopulations

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 SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460674

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 06, 2022

- -

Cardiomyopathy, familial restrictive, 6

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center

Jul 30, 2021

The paternally inherited c.1021G>A, p.Gly341Arg variant in the TAF1A gene in this affected child is a missense variant, which results in a substitution of Glycine residue to Arginine at position 341/451 of the protein, predicted to be damaging by multiple in silico prediction tools (SIFT and PROVEAN). This variant is rare from the gnomAD database with allele frequency 0.00002797 (7/250252 heterozygotes, 0 homozygote) indicating that it is not a common benign occurrence in the populations represented in the database. This variant has been previously reported in two cardiomyopathy sisters (2-3 years old) in compound heterozygous state with another missense variant in the TAF1A gene (PMID: 28472305). TAF1A encodes a TATA box-binding protein-associated factor which is required for RNA polymerase I to synthesize ribosomal RNA. In one study, the TAF1A gene specific subcellular phenotype was identified in approximately 50% of the cardiomyocytes of the affected sisters and was absent in pediatric normal and DCM controls. In a functional study of this gene, TAF1A-/- zebrafish recapitulate a heart failure phenotype (PMID: 28472305). However, since only one pediatric cardiomyopathy family has been reported with compound heterozygous TAF1A variants, the gene-disease association for TAF1A with pediatric cardiomyopathy remains uncertain. Given these evidences, TAF1A is a gene of unknown significance and therefore the c.1021G>A, p.Gly341Arg variant is classified as variant of unknown significance. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

.;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.86

D;T;.

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.7

.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.028

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.85

MutPred

0.47

.;Gain of MoRF binding (P = 0.012);Gain of MoRF binding (P = 0.012);

MVP

0.75

MPC

0.99

ClinPred

0.61

GERP RS

6.0

Varity_R

0.33

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over