chr5-173232936-T-G

Variant names:

• chr5-173232936-T-G
• rs771533553
• NM_004387.4:c.608A>C

Variant summary

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

The NM_004387.4(NKX2-5):​c.608A>C​(p.Glu203Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.608A>C	p.Glu203Ala	missense_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*407A>C		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*561A>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.608A>C	p.Glu203Ala	missense_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406	c.*561A>C		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848	c.*407A>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000440 AC: 1 AN: 227236 Hom.: 0 AF XY: 0.00000801 AC XY: 1 AN XY: 124856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000595

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 Cov.: 35

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.070
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.11	B
Vest4		0.55
MutPred		0.24		Gain of MoRF binding (P = 0.0606);
MVP		0.88
MPC		0.82
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.83
gMVP		0.77

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: rs771533553; hg19: chr5-172659939;