2-48620897-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006872.5(GTF2A1L):c.68G>A(p.Arg23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,603,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GTF2A1L
NM_006872.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

GTF2A1L (HGNC:30727): (general transcription factor IIA subunit 1 like) The assembly and stability of the RNA polymerase II transcription pre-initiation complex on a eukaryotic core promoter involve the effects of transcription factor IIA (TFIIA) on the interaction between TATA-binding protein (TBP) and DNA. This gene encodes a germ cell-specific counterpart of the large (alpha/beta) subunit of general transcription factor TFIIA that is able to stabilize the binding of TBP to DNA and may be uniquely important to testis biology. Alternative splicing for this locus has been observed and two variants, encoding distinct isoforms, have been identified. Co-transcription of this gene and the neighboring upstream gene generates a rare transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Mar 2014]

GTF2A1L links:

STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]

STON1-GTF2A1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.17149198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2A1L	NM_006872.5 link	c.68G>A	p.Arg23Gln	missense_variant	Exon 2 of 9	ENST00000403751.8	NP_006863.2	Q9UNN4-1A0A140VKA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2A1L	ENST00000403751.8 link	c.68G>A	p.Arg23Gln	missense_variant	Exon 2 of 9	1	NM_006872.5	ENSP00000384597.3		Q9UNN4-1
STON1-GTF2A1L	ENST00000394754.5 link	c.2180G>A	p.Arg727Gln	missense_variant	Exon 4 of 11	1		ENSP00000378236.1		Q53S48

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000779

AC:

AN:

243854

AF XY:

0.0000453

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000273

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000280

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1451610

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

721958

show subpopulations

African (AFR)

AF:

0.0000603

AC:

AN:

33148

American (AMR)

AF:

0.000254

AC:

AN:

43226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25922

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39106

South Asian (SAS)

AF:

0.0000356

AC:

AN:

84338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1107242

Other (OTH)

AF:

0.0000334

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41490

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.68G>A (p.R23Q) alteration is located in exon 2 (coding exon 2) of the GTF2A1L gene. This alteration results from a G to A substitution at nucleotide position 68, causing the arginine (R) at amino acid position 23 to be replaced by a glutamine (Q). 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

0.076

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

.;.;.;.;.;T

Eigen

Benign

0.062

Eigen_PC

Benign

0.069

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

.;D;D;D;D;D

M_CAP

Benign

0.082

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.8

.;.;.;.;.;M

PhyloP100

2.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N;N;N;D;D

REVEL

Benign

0.27

Sift

Benign

0.071

T;T;T;T;T;T

Sift4G

Benign

0.069

T;T;T;T;D;T

Polyphen

0.12

B;.;B;.;.;D

Vest4

0.42

MVP

0.38

MPC

0.013, 0.011

ClinPred

0.080

GERP RS

3.8

Varity_R

0.10

gMVP

0.42

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-48620897-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over