chr2-48646873-T-G

Position:

• chr2-48646873-T-G

Variant summary

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

The NM_006872.5(GTF2A1L):​c.809T>G​(p.Met270Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF2A1L NM_006872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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=0.1532372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2A1L	NM_006872.5	c.809T>G	p.Met270Arg	missense_variant	6/9	ENST00000403751.8
STON1-GTF2A1L	NM_001198593.2	c.2921T>G	p.Met974Arg	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2A1L	ENST00000403751.8	c.809T>G	p.Met270Arg	missense_variant	6/9	1	NM_006872.5	P1
GTF2A1L	ENST00000430487.6	c.707T>G	p.Met236Arg	missense_variant	5/8	2
GTF2A1L	ENST00000437125.5	c.836T>G	p.Met279Arg	missense_variant	6/6	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Mar 01, 2024

The c.809T>G (p.M270R) alteration is located in exon 6 (coding exon 6) of the GTF2A1L gene. This alteration results from a T to G substitution at nucleotide position 809, causing the methionine (M) at amino acid position 270 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.084	.;.;.;.;.;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.71	.;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;M
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.019	D;D;D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.30	B;.;B;.;.;P;P
Vest4		0.26
MutPred		0.55		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);.;.;.;.;
MVP		0.048
MPC		0.0057, 0.017
ClinPred		0.44	T
GERP RS		3.5
Varity_R		0.57
gMVP		0.35

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: rs1445275136; hg19: chr2-48874012;