7-74705211-G-A

Position:

• chr7-74705211-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032999.4(GTF2I):​c.634G>A​(p.Gly212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,532 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GTF2I NM_032999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108

Genes affected

GTF2I (HGNC:4659): (general transcription factor IIi) This gene encodes a phosphoprotein containing six characteristic repeat motifs. The encoded protein binds to the initiator element (Inr) and E-box element in promoters and functions as a regulator of transcription. This locus, along with several other neighboring genes, is deleted in Williams-Beuren syndrome. There are many closely related genes and pseudogenes for this gene on chromosome 7. This gene also has pseudogenes on chromosomes 9, 13, and 21. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Jul 2013]

GTF2I-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025761366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2I	NM_032999.4	c.634G>A	p.Gly212Ser	missense_variant	7/35	ENST00000573035.6	NP_127492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2I	ENST00000573035.6	c.634G>A	p.Gly212Ser	missense_variant	7/35	1	NM_032999.4	ENSP00000460070.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441532 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 08, 2024

The c.634G>A (p.G212S) alteration is located in exon 7 (coding exon 6) of the GTF2I gene. This alteration results from a G to A substitution at nucleotide position 634, causing the glycine (G) at amino acid position 212 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T;.;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.29	T;T;T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.070	.;.;.;.;N
REVEL	Benign	0.079
Sift	Benign	0.95	.;.;.;.;T
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.15
MutPred		0.22		Gain of glycosylation at G212 (P = 0.0122);Gain of glycosylation at G212 (P = 0.0122);Gain of glycosylation at G212 (P = 0.0122);Gain of glycosylation at G212 (P = 0.0122);Gain of glycosylation at G212 (P = 0.0122);
MVP		0.32
ClinPred		0.041	T
GERP RS		0.069
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.025
gMVP		0.33

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: rs886875869; hg19: chr7-74119543;