rs137852685

Positions:

chr5-173233062-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_004387.4(NKX2-5):c.482G>C(p.Arg161Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,603,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NKX2-5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity NKX25_HUMAN there are 47 pathogenic changes around while only 0 benign (100%) in NM_004387.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NKX2-5	NM_004387.4 linkuse as main transcript	c.482G>C	p.Arg161Pro	missense_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166175.2 linkuse as main transcript	c.*435G>C		3_prime_UTR_variant	2/2		NP_001159647.1
NKX2-5	NM_001166176.2 linkuse as main transcript	c.*281G>C		3_prime_UTR_variant	2/2		NP_001159648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.482G>C	p.Arg161Pro	missense_variant	2/2	1	NM_004387.4	ENSP00000327758	P1	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.*435G>C		3_prime_UTR_variant	2/2	1		ENSP00000395378		P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.*281G>C		3_prime_UTR_variant	2/2	2		ENSP00000427906		P52952-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000869

AC:

AN:

230216

Hom.:

AF XY:

0.0000160

AC XY:

AN XY:

125214

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000344

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1451422

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721346

show subpopulations

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:

0.0000822

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2006

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with thyroid dysgenesis in published literature (Dentice et al., 2006); Functional studies showed that p.(R161P) results in reduced activity of reporter genes and impaired DNA binding of NKX2-5 compared to wild-type (Dentice et al., 2006); This variant is associated with the following publications: (PMID: 27013732, 27152669, 35328834, 16418214) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.88

Vest4

0.58

MutPred

0.78

Loss of MoRF binding (P = 0.0048);

MVP

0.99

MPC

1.7

ClinPred

0.95

GERP RS

3.2

Varity_R

0.90

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over