NM_173537.5:c.209C>T

Variant names:

• chr7-74832834-G-A
• rs1169269263
• NM_173537.5:c.209C>T

Variant summary

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

The NM_173537.5(GTF2IRD2):​c.209C>T​(p.Thr70Met) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 9)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GTF2IRD2 NM_173537.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0310
• Publications: 0 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=0.041754693).

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.209C>T	p.Thr70Met	missense	Exon 3 of 16	NP_775808.4
	GTF2IRD2	NM_001368300.2		c.695C>T	p.Thr232Met	missense	Exon 4 of 17	NP_001355229.1	A0A494C0I1
	GTF2IRD2	NM_001388079.1		c.209C>T	p.Thr70Met	missense	Exon 3 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.209C>T	p.Thr70Met	missense	Exon 3 of 16	ENSP00000406723.3	Q86UP8-1
	ENSG00000289346	ENST00000625377.3	TSL:5	c.209C>T	p.Thr70Met	missense	Exon 10 of 23	ENSP00000486581.2
	GTF2IRD2	ENST00000614386.1	TSL:1	c.209C>T	p.Thr70Met	missense	Exon 3 of 3	ENSP00000481017.1	Q86UP8-4

Frequencies

GnomAD3 genomes AF: 0.0000148 AC: 1 AN: 67722 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.0000577

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000112 AC: 7 AN: 625404 Hom.: 0 Cov.: 8 AF XY: 0.00000606 AC XY: 2 AN XY: 329894

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

African (AFR) AF: 0.000118 AC: 2 AN: 16940

American (AMR) AF: 0.00 AC: 0 AN: 28032

Ashkenazi Jewish (ASJ) AF: 0.0000575 AC: 1 AN: 17394

East Asian (EAS) AF: 0.00 AC: 0 AN: 34972

South Asian (SAS) AF: 0.0000358 AC: 2 AN: 55812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2396

European-Non Finnish (NFE) AF: 0.00000514 AC: 2 AN: 388884

Other (OTH) AF: 0.00 AC: 0 AN: 32372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000624538), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000148 AC: 1 AN: 67722 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 31076

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

African (AFR) AF: 0.0000577 AC: 1 AN: 17318

American (AMR) AF: 0.00 AC: 0 AN: 5770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1910

East Asian (EAS) AF: 0.00 AC: 0 AN: 2292

South Asian (SAS) AF: 0.00 AC: 0 AN: 1422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33888

Other (OTH) AF: 0.00 AC: 0 AN: 790

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.031
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.069	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.23		Gain of catalytic residue at V66 (P = 0.0352)
MVP		0.014
ClinPred		0.070	T
GERP RS		-2.4
Varity_R		0.026
gMVP		0.043
Mutation Taster		=96/4	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: rs1169269263; hg19: chr7-74247957;