chr7-74512837-C-T

Variant names:

• chr7-74512837-C-T
• rs781866989
• NM_005685.4:c.131C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005685.4(GTF2IRD1):​c.131C>T​(p.Ala44Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000675 in 1,613,766 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: GTF2IRD1 NM_005685.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.02
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31811202).

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.131C>T	p.Ala44Val	missense	Exon 3 of 27	NP_005676.3
	GTF2IRD1	NM_001199207.2		c.131C>T	p.Ala44Val	missense	Exon 3 of 27	NP_001186136.1	Q9UHL9-3
	GTF2IRD1	NM_001410888.1		c.131C>T	p.Ala44Val	missense	Exon 3 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.131C>T	p.Ala44Val	missense	Exon 3 of 27	ENSP00000408477.2	Q9UHL9-2
	GTF2IRD1	ENST00000455841.6	TSL:1	c.131C>T	p.Ala44Val	missense	Exon 3 of 27	ENSP00000397566.2	Q9UHL9-3
	GTF2IRD1	ENST00000476977.5	TSL:1	c.131C>T	p.Ala44Val	missense	Exon 3 of 26	ENSP00000418383.1	E9PFE2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250932 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727088

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

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

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111850

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Benign	0.042	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.23		Gain of ubiquitination at K47 (P = 0.1278)
MVP		0.29
MPC		1.3
ClinPred		0.46	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.71
Mutation Taster		=70/30	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: rs781866989; hg19: chr7-73927167;