2-48646471-A-T

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.407A>T(p.Asn136Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,608,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N136S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

GTF2A1L
NM_006872.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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:

ENSG00000279956 (HGNC:):

ENSG00000279956 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=0.16877964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2A1L	NM_006872.5 link	c.407A>T	p.Asn136Ile	missense_variant	Exon 6 of 9	ENST00000403751.8	NP_006863.2	Q9UNN4-1A0A140VKA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GTF2A1L	ENST00000403751.8 link	c.407A>T	p.Asn136Ile	missense_variant	Exon 6 of 9	1	NM_006872.5	ENSP00000384597.3	Q9UNN4-1
STON1-GTF2A1L	ENST00000394754.5 link	c.2519A>T	p.Asn840Ile	missense_variant	Exon 8 of 11	1		ENSP00000378236.1	Q53S48
ENSG00000279956	ENST00000602369.3 link	n.*551T>A		non_coding_transcript_exon_variant	Exon 12 of 13	5		ENSP00000473498.1	R4GN57
ENSG00000279956	ENST00000602369.3 link	n.*551T>A		3_prime_UTR_variant	Exon 12 of 13	5		ENSP00000473498.1	R4GN57

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000738

AC:

AN:

243740

AF XY:

0.0000379

show subpopulations

Gnomad AFR exome

AF:

0.000621

Gnomad AMR exome

AF:

0.000239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1456800

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724706

show subpopulations

African (AFR)

AF:

0.000332

AC:

AN:

33104

American (AMR)

AF:

0.000207

AC:

AN:

43436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25722

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

85266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110454

Other (OTH)

AF:

0.00

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000138

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.000435

AC:

AN:

41386

American (AMR)

AF:

0.000197

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.407A>T (p.N136I) alteration is located in exon 6 (coding exon 6) of the GTF2A1L gene. This alteration results from a A to T substitution at nucleotide position 407, causing the asparagine (N) at amino acid position 136 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

.;.;.;.;.;.;.;T

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D;D;D;D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Pathogenic

3.0

.;.;.;.;.;.;.;M

PhyloP100

1.7

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;.;D;D

Vest4

0.73

MVP

0.37

MPC

0.010, 0.029

ClinPred

0.35

GERP RS

0.34

Varity_R

0.51

gMVP

0.78

Mutation Taster

=70/30

polymorphism

(source)

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

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2-48646471-A-T

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