rs606231353

chr4-13544077-GCC-GA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001189.4(NKX3-2):c.336_337delinsT(p.Ala113ProfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G112G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX3-2 NM_001189.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.134

Genes affected

NKX3-2 (HGNC:951): (NK3 homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; negative regulation of chondrocyte differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; embryonic skeletal system development; and intestinal epithelial cell development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.665 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 4-13544078-CC-A is Pathogenic according to our data. Variant chr4-13544078-CC-A is described in ClinVar as [Pathogenic]. Clinvar id is 7492.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX3-2	NM_001189.4	c.336_337delinsT	p.Ala113ProfsTer11	frameshift_variant	1/2	ENST00000382438.6
NKX3-2	XM_047416049.1	c.336_337delinsT	p.Ala113ProfsTer11	frameshift_variant	2/3
NKX3-2	XM_047416050.1	c.336_337delinsT	p.Ala113ProfsTer11	frameshift_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX3-2	ENST00000382438.6	c.336_337delinsT	p.Ala113ProfsTer11	frameshift_variant	1/2	1	NM_001189.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondylo-megaepiphyseal-metaphyseal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2009

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231353; hg19: chr4-13545702;