7-74518273-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_005685.4(GTF2IRD1):c.556C>T(p.Leu186Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GTF2IRD1 NM_005685.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

GTF2IRD1 (HGNC:4661): (GTF2I repeat domain containing 1) The protein encoded by this gene contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene plays a role in craniofacial and cognitive development and mutations have been associated with Williams-Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7q11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GTF2IRD1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTF2IRD1	NM_005685.4	c.556C>T	p.Leu186Phe	missense_variant	5/27	ENST00000424337.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTF2IRD1	ENST00000424337.7	c.556C>T	p.Leu186Phe	missense_variant	5/27	1	NM_005685.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Aug 17, 2022

The c.652C>T (p.L218F) alteration is located in exon 5 (coding exon 4) of the GTF2IRD1 gene. This alteration results from a C to T substitution at nucleotide position 652, causing the leucine (L) at amino acid position 218 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.73
MutPred		0.79		Gain of ubiquitination at K184 (P = 0.0985);.;Gain of ubiquitination at K184 (P = 0.0985);Gain of ubiquitination at K184 (P = 0.0985);
MVP		0.48
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.70
gMVP		0.78

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: chr7-73932603;