rs3729754

Variant names:

• chr5-173232912-G-A
• rs3729754
• NM_004387.4:c.632C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_004387.4(NKX2-5):​c.632C>T​(p.Pro211Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,603,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.45

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15610397).
• BP6: Variant 5-173232912-G-A is Benign according to our data. Variant chr5-173232912-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190836.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr5-173232912-G-A is described in Lovd as [Likely_benign]. Variant chr5-173232912-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000269 (41/152346) while in subpopulation NFE AF= 0.000485 (33/68032). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.632C>T	p.Pro211Leu	missense_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*431C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*585C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.632C>T	p.Pro211Leu	missense_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406	c.*585C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848	c.*431C>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000248 AC: 55 AN: 221568 Hom.: 0 AF XY: 0.000245 AC XY: 30 AN XY: 122328

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.0000626

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000367 AC: 533 AN: 1451642 Hom.: 0 Cov.: 35 AF XY: 0.000363 AC XY: 262 AN XY: 721682

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0000930

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.000451

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74492

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000239 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two related individuals with atrial septal defects and pacemakers, however, it was absent in two other affected family members (PMID: 12112663); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26334177, 31824610, 34070861, 35272499, 12112663, 31430255) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NKX2-5-related disorder Uncertain:1

Jun 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NKX2-5 c.632C>T variant is predicted to result in the amino acid substitution p.Pro211Leu. This variant has been reported in two family members with atrial septal defects however, this variant did not segregate with disease in two additional affected family members (Gutierrez-Roelens et al. 2002. PubMed ID: 12112663). This has also been reported with uncertain significance in two individuals with congenital hypothyroidism and in a healthy newborn; both individuals with congenital hypothyroidism had additional variants reported (Table 1, Santos-Silva et al. 2019. PubMed ID: 31430255; Table 1, Larrivée-Vanier et al. 2022. PubMed ID: 35272499; Table S4, Bodian et al. 2016. PubMed ID: 26334177). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Atrial septal defect 7 Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 05, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.0021
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.055	T
Sift4G	Uncertain	0.029	D
Polyphen		0.80	P
Vest4		0.39
MVP		0.79
MPC		1.4
ClinPred		0.099	T
GERP RS		3.7
Varity_R		0.24
gMVP		0.63

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

Other links and lift over

dbSNP: rs3729754; hg19: chr5-172659915; COSMIC: COSV105879885; COSMIC: COSV105879885;