7-74518158-C-G

Variant names:

• chr7-74518158-C-G
• rs112098981
• NM_005685.4:c.441C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005685.4(GTF2IRD1):​c.441C>G​(p.Ala147Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.000707 in 1,596,838 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 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: GTF2IRD1 NM_005685.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.63
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-74518158-C-G is Benign according to our data. Variant chr7-74518158-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 733730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.441C>G	p.Ala147Ala	synonymous	Exon 5 of 27	NP_005676.3
	GTF2IRD1	NM_001199207.2		c.537C>G	p.Ala179Ala	synonymous	Exon 5 of 27	NP_001186136.1	Q9UHL9-3
	GTF2IRD1	NM_001410888.1		c.441C>G	p.Ala147Ala	synonymous	Exon 5 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.441C>G	p.Ala147Ala	synonymous	Exon 5 of 27	ENSP00000408477.2	Q9UHL9-2
	GTF2IRD1	ENST00000455841.6	TSL:1	c.537C>G	p.Ala179Ala	synonymous	Exon 5 of 27	ENSP00000397566.2	Q9UHL9-3
	GTF2IRD1	ENST00000476977.5	TSL:1	c.441C>G	p.Ala147Ala	synonymous	Exon 5 of 26	ENSP00000418383.1	E9PFE2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000917 AC: 216 AN: 235520 AF XY: 0.000768

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000476 AC: 687 AN: 1444500 Hom.: 1 Cov.: 31 AF XY: 0.000440 AC XY: 315 AN XY: 716058

African (AFR) AF: 0.0113 AC: 374 AN: 33040

American (AMR) AF: 0.000827 AC: 36 AN: 43516

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 26 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 39188

South Asian (SAS) AF: 0.000200 AC: 17 AN: 85000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51852

Middle Eastern (MID) AF: 0.00381 AC: 20 AN: 5252

European-Non Finnish (NFE) AF: 0.000125 AC: 138 AN: 1101602

Other (OTH) AF: 0.00128 AC: 76 AN: 59378

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74492

African (AFR) AF: 0.00993 AC: 413 AN: 41574

American (AMR) AF: 0.000914 AC: 14 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00338

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GTF2IRD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.7
DANN	Benign	0.59
PhyloP100		3.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	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: rs112098981; hg19: chr7-73932488; COSMIC: COSV56091776;