NM_005685.4:c.39C>T

Variant names:

• chr7-74508119-C-T
• rs151198189
• NM_005685.4:c.39C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005685.4(GTF2IRD1):​c.39C>T​(p.Asn13Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00086 in 1,610,872 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (4 hom.)
• Consequence: GTF2IRD1 NM_005685.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540
• Publications: 3 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-74508119-C-T is Benign according to our data. Variant chr7-74508119-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 773212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.39C>T	p.Asn13Asn	synonymous	Exon 2 of 27	NP_005676.3
	GTF2IRD1	NM_001199207.2		c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 27	NP_001186136.1	Q9UHL9-3
	GTF2IRD1	NM_001410888.1		c.39C>T	p.Asn13Asn	synonymous	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.39C>T	p.Asn13Asn	synonymous	Exon 2 of 27	ENSP00000408477.2	Q9UHL9-2
	GTF2IRD1	ENST00000455841.6	TSL:1	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 27	ENSP00000397566.2	Q9UHL9-3
	GTF2IRD1	ENST00000476977.5	TSL:1	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 26	ENSP00000418383.1	E9PFE2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00115 AC: 286 AN: 248158 AF XY: 0.00124

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000845 AC: 1233 AN: 1458584 Hom.: 4 Cov.: 31 AF XY: 0.000876 AC XY: 636 AN XY: 725776

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00136 AC: 61 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 101 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86252

European-Finnish (FIN) AF: 0.000139 AC: 7 AN: 50294

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000854 AC: 950 AN: 1111908

Other (OTH) AF: 0.00121 AC: 73 AN: 60366

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74454

African (AFR) AF: 0.000409 AC: 17 AN: 41556

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		-0.054
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: rs151198189; hg19: chr7-73922449; COSMIC: COSV56086990;