7-74824984-C-T

Variant names:

• chr7-74824984-C-T
• rs375511371
• NM_173537.5:c.307G>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.307G>A​(p.Glu103Lys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: GTF2IRD2 NM_173537.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.68
• Publications: 2 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=0.0063505173).

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.307G>A	p.Glu103Lys	missense	Exon 4 of 16	NP_775808.4
	GTF2IRD2	NM_001368300.2		c.793G>A	p.Glu265Lys	missense	Exon 5 of 17	NP_001355229.1	A0A494C0I1
	GTF2IRD2	NM_001388079.1		c.307G>A	p.Glu103Lys	missense	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.307G>A	p.Glu103Lys	missense	Exon 4 of 16	ENSP00000406723.3	Q86UP8-1
	ENSG00000289346	ENST00000625377.3	TSL:5	c.307G>A	p.Glu103Lys	missense	Exon 11 of 23	ENSP00000486581.2
	GTF2IRD2	ENST00000651129.1		c.793G>A	p.Glu265Lys	missense	Exon 5 of 17	ENSP00000498563.1	A0A494C0I1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000986 AC: 118 AN: 119688 AF XY: 0.000729

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000565

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000200 AC: 1 AN: 500562 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 250290

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

African (AFR) AF: 0.00 AC: 0 AN: 5574

American (AMR) AF: 0.00 AC: 0 AN: 11224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8472

East Asian (EAS) AF: 0.00 AC: 0 AN: 3436

South Asian (SAS) AF: 0.00 AC: 0 AN: 31270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1698

European-Non Finnish (NFE) AF: 0.00000250 AC: 1 AN: 399534

Other (OTH) AF: 0.00 AC: 0 AN: 19274

⚠️ 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 Cov.: 0

Alfa AF: 0.000578 Hom.: 0

ESP6500AA AF: 0.00999 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000937 AC: 110

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.16
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.7
PrimateAI	Uncertain	0.65	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.061
ClinPred		0.059	T
GERP RS		2.7
Varity_R		0.084
gMVP		0.23
Mutation Taster		=84/16	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: rs375511371; hg19: chr7-74239513;