dbSNP rs606231354: NKX3-2:p.Ala35GlyfsTer87 (chr4-13544304-CCCGGGCG-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001189.4(NKX3-2):c.104_110delCGCCCGG(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. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NKX3-2
NM_001189.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

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

NKX3-2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 4-13544304-CCCGGGCG-C is Pathogenic according to our data. Variant chr4-13544304-CCCGGGCG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-2	NM_001189.4 link	c.104_110delCGCCCGG	p.Ala35GlyfsTer87	frameshift_variant	Exon 1 of 2	ENST00000382438.6	NP_001180.1	P78367
NKX3-2	XM_047416049.1 link	c.104_110delCGCCCGG	p.Ala35GlyfsTer87	frameshift_variant	Exon 2 of 3		XP_047272005.1
NKX3-2	XM_047416050.1 link	c.104_110delCGCCCGG	p.Ala35GlyfsTer87	frameshift_variant	Exon 2 of 3		XP_047272006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX3-2	ENST00000382438.6 link	c.104_110delCGCCCGG	p.Ala35GlyfsTer87	frameshift_variant	Exon 1 of 2	1	NM_001189.4	ENSP00000371875.5		P78367

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.24e-7

AC:

AN:

1381158

Hom.:

AF XY:

0.00000146

AC XY:

AN XY:

682684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29432

American (AMR)

AF:

0.00

AC:

AN:

33566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

35186

South Asian (SAS)

AF:

0.00

AC:

AN:

78708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4030

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079816

Other (OTH)

AF:

0.00

AC:

AN:

57410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondylo-megaepiphyseal-metaphyseal dysplasia

Pathogenic:2

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Sep 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with spondylo-megaepiphyseal-metaphyseal dysplasia (PMID: 20004766). ClinVar contains an entry for this variant (Variation ID: 7493). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=19/181

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over