NM_005685.4:c.32C>T

Variant names:

• chr7-74508112-C-T
• rs782139309
• NM_005685.4:c.32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005685.4(GTF2IRD1):​c.32C>T​(p.Pro11Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: GTF2IRD1 NM_005685.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82
• Publications: 1 publications found

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]

GTF2IRD1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19855648).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005685.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2IRD1	NM_005685.4	MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 2 of 27	NP_005676.3
	GTF2IRD1	NM_001199207.2		c.32C>T	p.Pro11Leu	missense	Exon 2 of 27	NP_001186136.1	Q9UHL9-3
	GTF2IRD1	NM_001410888.1		c.32C>T	p.Pro11Leu	missense	Exon 2 of 26	NP_001397817.1	E9PFE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2IRD1	ENST00000424337.7	TSL:1 MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 2 of 27	ENSP00000408477.2	Q9UHL9-2
	GTF2IRD1	ENST00000455841.6	TSL:1	c.32C>T	p.Pro11Leu	missense	Exon 2 of 27	ENSP00000397566.2	Q9UHL9-3
	GTF2IRD1	ENST00000476977.5	TSL:1	c.32C>T	p.Pro11Leu	missense	Exon 2 of 26	ENSP00000418383.1	E9PFE2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247766 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458126 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725574

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.0018
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.044
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.33	B
Vest4		0.43
MutPred		0.46		Gain of sheet (P = 0.0125)
MVP		0.11
MPC		1.3
ClinPred		0.53	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.34
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs782139309; hg19: chr7-73922442;