rs781871019

Variant names:

• chr7-74825050-C-T
• rs781871019
• NM_173537.5:c.241G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173537.5(GTF2IRD2):​c.241G>A​(p.Val81Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 12)
  • Exomes 𝑓: 0.000041 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: GTF2IRD2 NM_173537.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.914
• Publications: 1 publications found

Genes affected

GTF2IRD2 (HGNC:30775): (GTF2I repeat domain containing 2) This gene is one of several closely related genes on chromosome 7 encoding proteins containing helix-loop-helix motifs. These proteins may function as regulators of transcription. The encoded protein is unique in that its C-terminus is derived from CHARLIE8 transposable element sequence. This gene is located in a region of chromosome 7 that is deleted in Williams-Beuren syndrome, and loss of this locus may contribute to the cognitive phenotypes observed in this disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ENSG00000289346 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044751585).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173537.5. 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
	GTF2IRD2	NM_173537.5	MANE Select	c.241G>A	p.Val81Ile	missense splice_region	Exon 4 of 16	NP_775808.4
	GTF2IRD2	NM_001368300.2		c.727G>A	p.Val243Ile	missense splice_region	Exon 5 of 17	NP_001355229.1	A0A494C0I1
	GTF2IRD2	NM_001388079.1		c.241G>A	p.Val81Ile	missense splice_region	Exon 4 of 16	NP_001375008.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2IRD2	ENST00000451013.7	TSL:1 MANE Select	c.241G>A	p.Val81Ile	missense splice_region	Exon 4 of 16	ENSP00000406723.3	Q86UP8-1
	ENSG00000289346	ENST00000625377.3	TSL:5	c.241G>A	p.Val81Ile	missense splice_region	Exon 11 of 23	ENSP00000486581.2
	GTF2IRD2	ENST00000651129.1		c.727G>A	p.Val243Ile	missense splice_region	Exon 5 of 17	ENSP00000498563.1	A0A494C0I1

Frequencies

GnomAD3 genomes AF: 0.0000230 AC: 2 AN: 87072 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00

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: 0.0000434

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000895 AC: 10 AN: 111784 AF XY: 0.0000504

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: 0.000181

Gnomad OTH exome AF: 0.000397

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000414 AC: 39 AN: 941690 Hom.: 2 Cov.: 13 AF XY: 0.0000383 AC XY: 18 AN XY: 470124

African (AFR) AF: 0.000120 AC: 2 AN: 16618

American (AMR) AF: 0.00 AC: 0 AN: 19260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14428

East Asian (EAS) AF: 0.000100 AC: 1 AN: 9964

South Asian (SAS) AF: 0.00 AC: 0 AN: 59374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2628

European-Non Finnish (NFE) AF: 0.0000428 AC: 32 AN: 746832

Other (OTH) AF: 0.000113 AC: 4 AN: 35408

GnomAD4 genome AF: 0.0000230 AC: 2 AN: 87072 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 41302

African (AFR) AF: 0.00 AC: 0 AN: 18716

American (AMR) AF: 0.00 AC: 0 AN: 7602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2470

East Asian (EAS) AF: 0.00 AC: 0 AN: 2644

South Asian (SAS) AF: 0.00 AC: 0 AN: 2308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.0000434 AC: 2 AN: 46058

Other (OTH) AF: 0.00 AC: 0 AN: 1110

Alfa AF: 0.0000745 Hom.: 0

ExAC AF: 0.000110 AC: 13

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	Benign	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.11
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.91
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.30		Gain of methylation at K78 (P = 0.1138)
MVP		0.014
ClinPred		0.025	T
GERP RS		-5.4
Varity_R		0.011
gMVP		0.014
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781871019; hg19: chr7-74239579;