rs72554028

chr5-173233001-C-Gchr5-173233001-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004387.4(NKX2-5):c.543G>C(p.Gln181His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q181P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.37

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 chr5-173233002-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 5-173233001-C-G is Pathogenic according to our data. Variant chr5-173233001-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 36659.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-173233001-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.543G>C	p.Gln181His	missense_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.*496G>C		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2	c.*342G>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.543G>C	p.Gln181His	missense_variant	2/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.*496G>C		3_prime_UTR_variant	2/2	1
NKX2-5	ENST00000521848.1	c.*342G>C		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2016

Variant summary: The NKX2-5 c.543G>C (p.Gln181His) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and polar Glutamine (Q) with a medium size and polar Histidine (H). 4/5 in silico tools predict a damaging outcome for this substitution. This variant is absent in 90576 control chromosomes while it was reported in many atrioventricular conduction disease (AVCD) patients indicating pathogenicity. Moreover, in an AVCD family the variant was shown to co-segregate with the disease further supporting a deleterious outcome. In addition, a functional study demonstrated to variant to result in significantly decreased transcriptional activity at the atrial natriuretic factor promoter. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.88		Loss of disorder (P = 0.0575);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.97
gMVP		0.89

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: rs72554028; hg19: chr5-172660004;