rs606231354

chr4-13544304-CCCGGGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001189.4(NKX3-2):c.104_110del(p.Ala35GlyfsTer87) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A35A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NKX3-2 NM_001189.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.08

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 Pathogenic. Variant got 14 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 0.896 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-13544304-CCCGGGCG-C is Pathogenic according to our data. Variant chr4-13544304-CCCGGGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 7493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX3-2	NM_001189.4	c.104_110del	p.Ala35GlyfsTer87	frameshift_variant	1/2	ENST00000382438.6
NKX3-2	XM_047416049.1	c.104_110del	p.Ala35GlyfsTer87	frameshift_variant	2/3
NKX3-2	XM_047416050.1	c.104_110del	p.Ala35GlyfsTer87	frameshift_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX3-2	ENST00000382438.6	c.104_110del	p.Ala35GlyfsTer87	frameshift_variant	1/2	1	NM_001189.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381158 Hom.: 0 AF XY: 0.00000146 AC XY: 1 AN XY: 682684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylo-megaepiphyseal-metaphyseal dysplasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 18, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7493). This premature translational stop signal has been observed in individual(s) with spondylo-megaepiphyseal-metaphyseal dysplasia (PMID: 20004766). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala35Glyfs*87) in the NKX3-2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NKX3-2 are known to be pathogenic (PMID: 20004766). -

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: rs606231354; hg19: chr4-13545928;