10-8073745-AGA-CGC

Variant names:

• chr10-8073745-AGA-CGC
• NM_001002295.2:c.1057_1059delAGAinsCGC
• GATA3 p.354

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001441129.1(GATA3):​c.1051-2_1051delAGAinsCGC​(p.Thr351Pro) variant causes a splice acceptor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T351N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GATA3 NM_001441129.1 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

GATA3 (HGNC:4172): (GATA binding protein 3) This gene encodes a protein which belongs to the GATA family of transcription factors. The protein contains two GATA-type zinc fingers and is an important regulator of T-cell development and plays an important role in endothelial cell biology. Defects in this gene are the cause of hypoparathyroidism with sensorineural deafness and renal dysplasia. [provided by RefSeq, Nov 2009]

GATA3 Gene-Disease associations (from GenCC):

• hypoparathyroidism-deafness-renal disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.3152174 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of -8, new splice context is: aaaaattgatctttgtttAGatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441129.1. 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
	GATA3	NM_001002295.2	MANE Select	c.1057_1059delAGAinsCGC	p.354	synonymous	N/A	NP_001002295.1	P23771-2
	GATA3	NM_001441115.1		c.1057_1059delAGAinsCGC	p.354	synonymous	N/A	NP_001428044.1
	GATA3	NM_001441116.1		c.1057_1059delAGAinsCGC	p.354	synonymous	N/A	NP_001428045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA3	ENST00000379328.9	TSL:1 MANE Select	c.1057_1059delAGAinsCGC	p.354	synonymous	N/A	ENSP00000368632.3	P23771-2
	GATA3	ENST00000346208.4	TSL:1	c.1054_1056delAGAinsCGC	p.353	synonymous	N/A	ENSP00000341619.3	P23771-1
	GATA3	ENST00000872595.1		c.1057_1059delAGAinsCGC	p.354	synonymous	N/A	ENSP00000542654.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-8115708;