chr2-48617882-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006872.5(GTF2A1L):c.8G>T(p.Cys3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C3S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GTF2A1L
NM_006872.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.949

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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04250428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2A1L	NM_006872.5 link	c.8G>T	p.Cys3Phe	missense_variant	Exon 1 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.8G>T	p.Cys3Phe	missense_variant	Exon 1 of 9	1	NM_006872.5	ENSP00000384597.3		Q9UNN4-1
STON1-GTF2A1L	ENST00000394754.5 link	c.2134-2969G>T		intron_variant	Intron 3 of 10	1		ENSP00000378236.1		Q53S48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000647

AC:

AN:

154574

AF XY:

0.0000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000917

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399476

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690256

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.0000280

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079012

Other (OTH)

AF:

0.00

AC:

AN:

58018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.19

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.043

.;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.33

T;T;T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

.;.;N;N

PhyloP100

-0.95

PROVEAN

Benign

0.25

N;N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.71

T;T;T;T

Sift4G

Benign

0.72

.;T;.;T

Polyphen

0.0

.;.;B;B

Vest4

0.084, 0.091

MutPred

0.32

Loss of catalytic residue at M1 (P = 1e-04);Loss of catalytic residue at M1 (P = 1e-04);Loss of catalytic residue at M1 (P = 1e-04);Loss of catalytic residue at M1 (P = 1e-04);

MVP

0.15

MPC

0.0055

ClinPred

0.028

GERP RS

-7.0

PromoterAI

0.11

Neutral

(source)

Varity_R

0.041

gMVP

0.19

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over