rs1009994744

Variant names:

• chr5-173234804-G-A
• rs1009994744
• NM_004387.4:c.280C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004387.4(NKX2-5):​c.280C>T​(p.Pro94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.77

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094860405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2		NP_001159647.1
NKX2-5	XM_017009071.3	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2	2		ENSP00000427906.1
NKX2-5	ENST00000517440.1	c.280C>T	p.Pro94Ser	missense_variant	Exon 1 of 2	4		ENSP00000429905.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

NKX2-5-related disorder Uncertain:1

Sep 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NKX2-5 c.280C>T variant is predicted to result in the amino acid substitution p.Pro94Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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 Uncertain:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 94 of the NKX2-5 protein (p.Pro94Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. ClinVar contains an entry for this variant (Variation ID: 468242). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NKX2-5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.5	L;L;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.27	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.76	T;T;T;.
Polyphen		0.0	B;.;.;B
Vest4		0.087
MutPred		0.18		Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);
MVP		0.65
MPC		1.4
ClinPred		0.088	T
GERP RS		0.30
Varity_R		0.024
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1009994744; hg19: chr5-172661807;