rs2267831

Variant names:

• chr7-74506190-G-C
• rs2267831
• ENST00000476977.5:c.-1493G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000476977.5(GTF2IRD1):​c.-1493G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,200 control chromosomes in the GnomAD database, including 2,033 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (2033 hom., cov: 32)
  • Exomes 𝑓: 0.036 (0 hom.)
• Consequence: GTF2IRD1 ENST00000476977.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000476977.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2IRD1	NM_005685.4	MANE Select	c.-6-1885G>C		intron	N/A	NP_005676.3
	GTF2IRD1	NM_001199207.2		c.-6-1885G>C		intron	N/A	NP_001186136.1
	GTF2IRD1	NM_001410888.1		c.-6-1885G>C		intron	N/A	NP_001397817.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2IRD1	ENST00000476977.5	TSL:1	c.-1493G>C		5_prime_UTR	Exon 1 of 26	ENSP00000418383.1
	GTF2IRD1	ENST00000424337.7	TSL:1 MANE Select	c.-6-1885G>C		intron	N/A	ENSP00000408477.2
	GTF2IRD1	ENST00000455841.6	TSL:1	c.-6-1885G>C		intron	N/A	ENSP00000397566.2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15798 AN: 152054 Hom.: 2027 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.0789

GnomAD4 exome AF: 0.0357 AC: 1 AN: 28 Hom.: 0 Cov.: 0 AF XY: 0.0500 AC XY: 1 AN XY: 20

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.100 AC: 1 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.104 AC: 15828 AN: 152172 Hom.: 2033 Cov.: 32 AF XY: 0.105 AC XY: 7811 AN XY: 74390

African (AFR) AF: 0.270 AC: 11217 AN: 41496

American (AMR) AF: 0.112 AC: 1720 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.388 AC: 1994 AN: 5142

South Asian (SAS) AF: 0.0477 AC: 230 AN: 4822

European-Finnish (FIN) AF: 0.0172 AC: 183 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 68010

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0547 Hom.: 120

Bravo AF: 0.118

Asia WGS AF: 0.208 AC: 723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-0.15
PromoterAI		-0.010	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2267831; hg19: chr7-73920520;