chr5-173233167-T-G

Variant names:

• chr5-173233167-T-G
• rs1320947604
• NM_004387.4:c.377A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_004387.4(NKX2-5):​c.377A>C​(p.Glu126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E126V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.54

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2270866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.377A>C	p.Glu126Ala	missense_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*176A>C		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*330A>C		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.377A>C	p.Glu126Ala	missense_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406	c.*330A>C		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848	c.*176A>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000432 AC: 1 AN: 231614 Hom.: 0 AF XY: 0.00000786 AC XY: 1 AN XY: 127180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451062 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Uncertain:1

Nov 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NKX2-5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 126 of the NKX2-5 protein (p.Glu126Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. 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. -

not provided Uncertain:1

Dec 18, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

NKX2-5, Exon 2, c.377A>C (p.Glu126Ala) (NM_004387.3; chr5-172660170-T-G) Seen in a family in our center with DCM who also have a likely pathogenic A band frameshift in TTN. SCICD Classification: variant of uncertain significance based on limited data to associate this gene with this disease, lack of case data and presence in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Costa al (2013) were the first to look at NKX2.5 in DCM. They sequenced NKX2.5 in 220 DCM probands and found one missense that they felt was disease causing (1/220), p.Ile184Met. The proband had normal sequencing of key DCM genes. Three family members had DCM and all carried the variant. Another family member had conduction system disease without other cardiac findings and also carried the variant. All of the three family members with DCM also had phenotypes previously associated with NKX2.5 including conduction system disease and congenital heart defects. Yuan et al (2015) sequenced NKX2.5 in 130 probands with DCM and found one suspicious variant, p.Ser146Trp (0.77% frequency). A total of three family members with DCM were positive for the variant. The probands father had DCM and was deceased. The proband's mother tested positive for the variant, suggesting it was inherited from the father. The family phenotype also included atrial fibrillation, atrioventricular block, premature ventricular contractions, and sudden death. Patrick Ellinor's group reported on two families with NKX2.5 variants segregating with cardiac phenotypes, including DCM. In both cases exome sequencing was used to identify the variant. Xu et al (2017) sequenced NKX2.5 in 210 unrelated patients with "sporadic adult-onset" DCM and found suspicious variants in 2 individuals (0.95% frequency). Both had atrial septal defect and progressive atrioventricular block. Interestingly, in both cases the variants were de novo and the parents did not have DCM. Family 186 had p.Ile184Phe, Family 187 had p.Ile184Met (previously reported by Costa et al 2013, absent in gnomAD). Phenotypes in both families included DCM, VSD, ASD, AV block. In family 186 the individuals with DCM did not have the other phenotypes. The variant was present in two affected siblings and their affected uncle. Their mother was also affected. In family 187 the variant was present in a male with DCM, his son with ASD, and his cousin with DCM. Another cousin (different branch) had VSD but did not have the variant (the authors interpreted this as a sporadic phenotype). Another cousin (yet another distinct branch) had polymorphic NSVT in the setting of heavy caffeine intake, but didn't have the variant. Related genes have been reported in association with cardiomyopathy, though we did not assess the strength of evidence (ex. TBX20, GATA4, TBX5, GATA5, HAND1. Case data (not including our patient): none reported Segregation data: none reported Functional data: none reported Population data: Highest MAF in gnomAD Latino population: 0.003034%. The variant was reported online in 1 of 16478 Latino individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. It was not seen in any other groups in gnomAD. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.67
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.71	T
Sift4G	Benign	0.65	T
Polyphen		0.65	P
Vest4		0.11
MutPred		0.17		Gain of MoRF binding (P = 0.0237);
MVP		0.79
MPC		0.54
ClinPred		0.16	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.36

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: rs1320947604; hg19: chr5-172660170;