rs137852685

Variant names:

• chr5-173233062-C-A
• NM_004387.4:c.482G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-173233062-C-A
• chr5-173233062-C-G
• chr5-173233062-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_004387.4(NKX2-5):​c.482G>T​(p.Arg161Leu) 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 1,451,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity NKX25_HUMAN there are 47 pathogenic changes around while only 0 benign (100%) in NM_004387.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-173233062-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.482G>T	p.Arg161Leu	missense_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*281G>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*435G>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.482G>T	p.Arg161Leu	missense_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406	c.*435G>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848	c.*281G>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451422 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 721346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.59	P
Vest4		0.48
MutPred		0.68		Loss of MoRF binding (P = 0.0266);
MVP		0.92
MPC		1.5
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.88
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-172660065;