7-74700415-C-T

Position:

• chr7-74700415-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032999.4(GTF2I):​c.542C>T​(p.Ser181Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF2I NM_032999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF2I	NM_032999.4	c.542C>T	p.Ser181Leu	missense_variant	5/35	ENST00000573035.6	NP_127492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF2I	ENST00000573035.6	c.542C>T	p.Ser181Leu	missense_variant	5/35	1	NM_032999.4	ENSP00000460070.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 15, 2024

The c.542C>T (p.S181L) alteration is located in exon 5 (coding exon 4) of the GTF2I gene. This alteration results from a C to T substitution at nucleotide position 542, causing the serine (S) at amino acid position 181 to be replaced by a leucine (L). 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	0.23
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	.;.;.;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.022	.;.;.;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.76
MutPred		0.59		Loss of methylation at K177 (P = 0.0697);Loss of methylation at K177 (P = 0.0697);Loss of methylation at K177 (P = 0.0697);Loss of methylation at K177 (P = 0.0697);Loss of methylation at K177 (P = 0.0697);
MVP		0.57
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.34
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-74114745;