4-13544077-G-GC

Variant names:

• chr4-13544077-G-GC
• rs606231352
• NM_001189.4:c.337dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001189.4(NKX3-2):​c.337dupG​(p.Ala113GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,427,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NKX3-2 NM_001189.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.134
• Publications: 0 publications found

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]

NKX3-2 Gene-Disease associations (from GenCC):

• spondylo-megaepiphyseal-metaphyseal dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-13544077-G-GC is Pathogenic according to our data. Variant chr4-13544077-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 7491.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001189.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-2	NM_001189.4	MANE Select	c.337dupG	p.Ala113GlyfsTer19	frameshift	Exon 1 of 2	NP_001180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-2	ENST00000382438.6	TSL:1 MANE Select	c.337dupG	p.Ala113GlyfsTer19	frameshift	Exon 1 of 2	ENSP00000371875.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1427908 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707692

African (AFR) AF: 0.00 AC: 0 AN: 31644

American (AMR) AF: 0.00 AC: 0 AN: 40306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 37654

South Asian (SAS) AF: 0.00 AC: 0 AN: 81902

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097668

Other (OTH) AF: 0.00 AC: 0 AN: 58898

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

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs606231352; hg19: chr4-13545701;