chr2-48621265-G-C

Position:

• chr2-48621265-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006872.5(GTF2A1L):​c.222G>C​(p.Leu74Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GTF2A1L NM_006872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.748

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1331181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2A1L	NM_006872.5	c.222G>C	p.Leu74Phe	missense_variant	3/9	ENST00000403751.8	NP_006863.2
STON1-GTF2A1L	NM_001198593.2	c.2334G>C	p.Leu778Phe	missense_variant	5/11		NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2A1L	ENST00000403751.8	c.222G>C	p.Leu74Phe	missense_variant	3/9	1	NM_006872.5	ENSP00000384597	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 06, 2022

The c.222G>C (p.L74F) alteration is located in exon 3 (coding exon 3) of the GTF2A1L gene. This alteration results from a G to C substitution at nucleotide position 222, causing the leucine (L) at amino acid position 74 to be replaced by a phenylalanine (F). 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	0.075
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	.;.;.;.;.;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	.;T;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;M
MutationTaster	Benign	0.98	N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.11	N;N;N;N;N;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.24	T;T;T;T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;T;T;T;T
Polyphen		0.010	B;.;B;.;.;.;D;D
Vest4		0.31
MutPred		0.57		Gain of loop (P = 0.024);Gain of loop (P = 0.024);Gain of loop (P = 0.024);Gain of loop (P = 0.024);.;.;.;.;
MVP		0.067
MPC		0.011, 0.019
ClinPred		0.53	D
GERP RS		1.8
Varity_R		0.035
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs1675984423; hg19: chr2-48848404;