rs1009994744

chr5-173234804-G-A

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 (★). Synonymous variant affecting the same amino acid position (i.e. P94P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.280C>T	p.Pro94Ser	missense_variant	1/2	ENST00000329198.5
NKX2-5	NM_001166176.2	c.280C>T	p.Pro94Ser	missense_variant	1/2
NKX2-5	NM_001166175.2	c.280C>T	p.Pro94Ser	missense_variant	1/2
NKX2-5	XM_017009071.3	c.280C>T	p.Pro94Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.280C>T	p.Pro94Ser	missense_variant	1/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.280C>T	p.Pro94Ser	missense_variant	1/2	1
NKX2-5	ENST00000521848.1	c.280C>T	p.Pro94Ser	missense_variant	1/2	2
NKX2-5	ENST00000517440.1	c.280C>T	p.Pro94Ser	missense_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NKX2-5-related disease. This sequence change replaces proline with serine at codon 94 of the NKX2-5 protein (p.Pro94Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. -

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;.
MutationTaster	Benign	1.0	N;N;N
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;