rs387906775

Positions:

• chr5-173234909-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004387.4(NKX2-5):​c.175C>G​(p.Pro59Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.69

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
• PP5: Variant 5-173234909-G-C is Pathogenic according to our data. Variant chr5-173234909-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 30116.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-173234909-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38803738). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.175C>G	p.Pro59Ala	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.175C>G	p.Pro59Ala	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.175C>G	p.Pro59Ala	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3	c.175C>G	p.Pro59Ala	missense_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.175C>G	p.Pro59Ala	missense_variant	1/2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.175C>G	p.Pro59Ala	missense_variant	1/2	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.175C>G	p.Pro59Ala	missense_variant	1/2	2		ENSP00000427906.1
NKX2-5	ENST00000517440.1	c.175C>G	p.Pro59Ala	missense_variant	1/2	4		ENSP00000429905.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723966

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ventricular septal defect 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	L;L;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.52	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	0.63	T;T;T;.
Polyphen		0.63	P;.;.;B
Vest4		0.70
MutPred		0.21		Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);
MVP		0.90
MPC		1.4
ClinPred		0.69	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.30

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: rs387906775; hg19: chr5-172661912;