Genetic Variant NKX3-2:c.*176T>C (chr4-13541817-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001189.4(NKX3-2):c.*176T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 988,806 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.015 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 32 hom. )

Consequence

NKX3-2
NM_001189.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.29

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

NKX3-2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-13541817-A-G is Benign according to our data. Variant chr4-13541817-A-G is described in ClinVar as Benign. ClinVar VariationId is 1257751.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-2	NM_001189.4	MANE Select	c.*176T>C		3_prime_UTR	Exon 2 of 2	NP_001180.1	P78367

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-2	ENST00000382438.6	TSL:1 MANE Select	c.*176T>C		3_prime_UTR	Exon 2 of 2	ENSP00000371875.5	P78367

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2238

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0148

GnomAD4 exome

AF:

0.00159

AC:

1334

AN:

836424

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

616

AN XY:

416942

show subpopulations

African (AFR)

AF:

0.0532

AC:

1032

AN:

19400

American (AMR)

AF:

0.00333

AC:

AN:

19546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15884

East Asian (EAS)

AF:

0.00

AC:

AN:

32060

South Asian (SAS)

AF:

0.000216

AC:

AN:

51030

European-Finnish (FIN)

AF:

0.0000545

AC:

AN:

36668

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

2788

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

620702

Other (OTH)

AF:

0.00402

AC:

154

AN:

38346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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

AF:

0.0147

AC:

2233

AN:

152382

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1041

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.0507

AC:

2109

AN:

41598

American (AMR)

AF:

0.00509

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68044

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

232

347

463

579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0244

Hom.:

Bravo

AF:

0.0170

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.5

(source)

DANN

Benign

0.68

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over