NM_005685.4:c.973C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_005685.4(GTF2IRD1):c.973C>T(p.Arg325Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GTF2IRD1
NM_005685.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.38

Publications

2 publications found

Variant links:

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

GTF2IRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

PP5

Variant 7-74521264-C-T is Pathogenic according to our data. Variant chr7-74521264-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208388.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GTF2IRD1	NM_005685.4	MANE Select	c.973C>T	p.Arg325Cys	missense	Exon 7 of 27	NP_005676.3
GTF2IRD1	NM_001199207.2		c.1069C>T	p.Arg357Cys	missense	Exon 7 of 27	NP_001186136.1
GTF2IRD1	NM_001410888.1		c.973C>T	p.Arg325Cys	missense	Exon 7 of 26	NP_001397817.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GTF2IRD1	ENST00000424337.7	TSL:1 MANE Select	c.973C>T	p.Arg325Cys	missense	Exon 7 of 27	ENSP00000408477.2
GTF2IRD1	ENST00000455841.6	TSL:1	c.1069C>T	p.Arg357Cys	missense	Exon 7 of 27	ENSP00000397566.2
GTF2IRD1	ENST00000476977.5	TSL:1	c.973C>T	p.Arg325Cys	missense	Exon 7 of 26	ENSP00000418383.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459110

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109802

Other (OTH)

AF:

0.00

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Childhood-onset schizophrenia

Pathogenic:1

Jan 01, 2014

Dr. Guy Rouleau's laboratory, McGill University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.73

PhyloP100

3.4

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.80

MutPred

0.53

Gain of sheet (P = 4e-04)

MVP

0.46

MPC

1.5

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.82

Mutation Taster

=58/42

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over