chr14-81192559-T-A

Position:

• chr14-81192559-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015859.4(GTF2A1):​c.893A>T​(p.Asp298Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF2A1 NM_015859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

Genes affected

GTF2A1 (HGNC:4646): (general transcription factor IIA subunit 1) Accurate transcription initiation on TATA-containing class II genes involves the ordered assembly of RNA polymerase II (POLR2A; MIM 180660) and several general initiation factors (summarized by DeJong and Roeder, 1993 [PubMed 8224848]). One of these factors is TFIIA, which when purified from HeLa extracts consists of 35-, 19-, and 12-kD subunits.[supplied by OMIM, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26994514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2A1	NM_015859.4	c.893A>T	p.Asp298Val	missense_variant	7/9	ENST00000553612.6	NP_056943.1
GTF2A1	NM_201595.3	c.776A>T	p.Asp259Val	missense_variant	7/9		NP_963889.1
GTF2A1	NM_001278940.2	c.743A>T	p.Asp248Val	missense_variant	8/10		NP_001265869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2A1	ENST00000553612.6	c.893A>T	p.Asp298Val	missense_variant	7/9	1	NM_015859.4	ENSP00000452454	P1
GTF2A1	ENST00000434192.2	c.776A>T	p.Asp259Val	missense_variant	7/9	1		ENSP00000409492
GTF2A1	ENST00000298173.7	c.*780A>T		3_prime_UTR_variant, NMD_transcript_variant	8/10	2		ENSP00000298173

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 09, 2023

The c.893A>T (p.D298V) alteration is located in exon 7 (coding exon 7) of the GTF2A1 gene. This alteration results from a A to T substitution at nucleotide position 893, causing the aspartic acid (D) at amino acid position 298 to be replaced by a valine (V). 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	Benign	0.28
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.71	P;.
Vest4		0.41
MutPred		0.55		Gain of helix (P = 0.0696);.;
MVP		0.22
MPC		0.054
ClinPred		0.92	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.29
gMVP		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-81658903;