rs746594822
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The ENST00000329198.5(NKX2-5):c.111G>A(p.Leu37=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,612,008 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000076 ( 0 hom. )
Consequence
NKX2-5
ENST00000329198.5 synonymous
ENST00000329198.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.483
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 5-173234973-C-T is Benign according to our data. Variant chr5-173234973-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505440.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BP7
Synonymous conserved (PhyloP=0.483 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | NP_001159648.1 | ||
NKX2-5 | NM_001166175.2 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | NP_001159647.1 | ||
NKX2-5 | XM_017009071.3 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | XP_016864560.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | 1 | NM_004387.4 | ENSP00000327758 | P1 | |
NKX2-5 | ENST00000424406.2 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | 1 | ENSP00000395378 | |||
NKX2-5 | ENST00000521848.1 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | 2 | ENSP00000427906 | |||
NKX2-5 | ENST00000517440.1 | c.111G>A | p.Leu37= | synonymous_variant | 1/2 | 4 | ENSP00000429905 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
2
AN:
152226
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 241766Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132730
GnomAD3 exomes
AF:
AC:
3
AN:
241766
Hom.:
AF XY:
AC XY:
2
AN XY:
132730
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000760 AC: 111AN: 1459782Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 726226
GnomAD4 exome
AF:
AC:
111
AN:
1459782
Hom.:
Cov.:
31
AF XY:
AC XY:
50
AN XY:
726226
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
GnomAD4 genome
AF:
AC:
2
AN:
152226
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
74366
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 15, 2016 | The p.Leu37Leu variant in NKX2-5 has not been previously reported in patients an d has been identified in 1/110,814 of chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs746594822). Although this v ariant has been seen once in the general population, its frequency is not high e nough to rule out a pathogenic role. The NKX2-5 gene has been associated with va rious congenital heart defects. To date, two different missense variants in NKX2 -5 have been reported in two individuals with hypoplastic left heart syndrome, o ne of which was also identified in a family member with atrial septal defect (El liott 2003 and McElhinney 2003). Although the variant is silent with no predicte d change in amino acid sequence, computational tools predict with moderate stren gth a possible new splice site which could lead to loss of a substantive portion of the protein. It should be noted that this is an unvalidated prediction only, without biological support, and therefore one cannot assume a splicing impact. In summary, the clinical significance of the c.111G>A variant is uncertain at th is time but we cannot rule out pathogenicity of this variant and possible contri bution to the hypoplastic left heart phenotype observed in this patient. - |
Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C2673630:Hypothyroidism, congenital, nongoitrous, 5;C3276096:Atrial septal defect 7;C3280785:Ventricular septal defect 3;C3280795:Hypoplastic left heart syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Atrial septal defect 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at