2-48646457-C-G

Variant names:

• chr2-48646457-C-G
• rs372106551
• NM_006872.5:c.393C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006872.5(GTF2A1L):​c.393C>G​(p.His131Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF2A1L NM_006872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200

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]

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]

ENSG00000279956 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081608236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTF2A1L	NM_006872.5	c.393C>G	p.His131Gln	missense_variant	Exon 6 of 9	ENST00000403751.8	NP_006863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTF2A1L	ENST00000403751.8	c.393C>G	p.His131Gln	missense_variant	Exon 6 of 9	1	NM_006872.5	ENSP00000384597.3
STON1-GTF2A1L	ENST00000394754.5	c.2505C>G	p.His835Gln	missense_variant	Exon 8 of 11	1		ENSP00000378236.1
ENSG00000279956	ENST00000602369.3	n.*565G>C		non_coding_transcript_exon_variant	Exon 12 of 13	5		ENSP00000473498.1
ENSG00000279956	ENST00000602369.3	n.*565G>C		3_prime_UTR_variant	Exon 12 of 13	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442134 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716696

African (AFR) AF: 0.00 AC: 0 AN: 32252

American (AMR) AF: 0.00 AC: 0 AN: 39778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 82190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105384

Other (OTH) AF: 0.00 AC: 0 AN: 59538

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.393C>G (p.H131Q) alteration is located in exon 6 (coding exon 6) of the GTF2A1L gene. This alteration results from a C to G substitution at nucleotide position 393, causing the histidine (H) at amino acid position 131 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	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.056	.;.;.;.;.;.;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.71	.;T;T;T;T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;.;.;.;.;L
PhyloP100		-0.020
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.12	B;.;B;.;.;.;B;B
Vest4		0.24
MutPred		0.58		Loss of ubiquitination at K838 (P = 0.1072);Loss of ubiquitination at K838 (P = 0.1072);Loss of ubiquitination at K838 (P = 0.1072);.;.;.;.;.;
MVP		0.081
MPC		0.0036, 0.0076
ClinPred		0.29	T
GERP RS		2.2
Varity_R		0.049
gMVP		0.49
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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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Other links and lift over

dbSNP: rs372106551; hg19: chr2-48873596;