chr15-59650685-T-A

Position:

• chr15-59650685-T-A

Variant summary

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

The NM_004492.3(GTF2A2):​c.161A>T​(p.Asn54Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,024 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF2A2 NM_004492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

Genes affected

GTF2A2 (HGNC:4647): (general transcription factor IIA subunit 2) Accurate transcription initiation on TATA-containing class II genes involves the ordered assembly of RNA polymerase II (POLR2A; MIM 180660) and the general initiation factors TFIIA, TFIIB (MIM 189963), TFIID (MIM 313650), TFIIE (MIM 189962), TFIIF (MIM 189968), TFIIG/TFIIJ, and TFIIH (MIM 189972). The first step involves recognition of the TATA element by the TATA-binding subunit (TBP; MIM 600075) and may be regulated by TFIIA, a factor that interacts with both TBP and a TBP-associated factor (TAF; MIM 600475) in TFIID. TFIIA has 2 subunits (43 and 12 kD) in yeast and 3 subunits in higher eukaryotes. In HeLa extracts, it consists of a 35-kD alpha subunit and a 19-kD beta subunit encoded by the N- and C-terminal regions of GTF2A1 (MIM 600520), respectively, and a 12-kD gamma subunit encoded by GTF2A2 (DeJong et al., 1995 [PubMed 7724559]).[supplied by OMIM, Mar 2008]

ENSG00000227161 (HGNC:):

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, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2A2	NM_004492.3	c.161A>T	p.Asn54Ile	missense_variant	3/5	ENST00000396060.7	NP_004483.1
GTF2A2	NM_001320929.2	c.161A>T	p.Asn54Ile	missense_variant	3/5		NP_001307858.1
GTF2A2	NM_001320930.2	c.161A>T	p.Asn54Ile	missense_variant	4/6		NP_001307859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2A2	ENST00000396060.7	c.161A>T	p.Asn54Ile	missense_variant	3/5	1	NM_004492.3	ENSP00000379372.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441024 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 718416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jul 23, 2024

The c.161A>T (p.N54I) alteration is located in exon 3 (coding exon 2) of the GTF2A2 gene. This alteration results from a A to T substitution at nucleotide position 161, causing the asparagine (N) at amino acid position 54 to be replaced by an isoleucine (I). 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	0.86
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	.;D;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.5	M;.;M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;.
Polyphen		0.92	P;.;P;P;.
Vest4		0.87
MutPred		0.57		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.50
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1891763910; hg19: chr15-59942884;