Genetic Variant NKX3-2:p.Ala113GlyfsTer19 (chr4-13544077-G-GC) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

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

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.134

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-2	NM_001189.4 link	c.337dupG	p.Ala113GlyfsTer19	frameshift_variant	Exon 1 of 2	ENST00000382438.6	NP_001180.1	P78367
NKX3-2	XM_047416049.1 link	c.337dupG	p.Ala113GlyfsTer19	frameshift_variant	Exon 2 of 3		XP_047272005.1
NKX3-2	XM_047416050.1 link	c.337dupG	p.Ala113GlyfsTer19	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.337dupG	p.Ala113GlyfsTer19	frameshift_variant	Exon 1 of 2	1	NM_001189.4	ENSP00000371875.5		P78367

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1427908

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31644

American (AMR)

AF:

0.00

AC:

AN:

40306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25078

East Asian (EAS)

AF:

0.00

AC:

AN:

37654

South Asian (SAS)

AF:

0.00

AC:

AN:

81902

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1097668

Other (OTH)

AF:

0.00

AC:

AN:

58898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.13

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

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

Publications

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4-13544077-GC-GCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over