chr5-173234973-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_004387.4(NKX2-5):c.111G>A(p.Leu37Leu) 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
Consequence
NM_004387.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | NP_001159648.1 | ||
NKX2-5 | NM_001166175.2 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | NP_001159647.1 | ||
NKX2-5 | XM_017009071.3 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | XP_016864560.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406.2 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | 1 | ENSP00000395378.2 | |||
NKX2-5 | ENST00000521848.1 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | 2 | ENSP00000427906.1 | |||
NKX2-5 | ENST00000517440.1 | c.111G>A | p.Leu37Leu | synonymous_variant | Exon 1 of 2 | 4 | ENSP00000429905.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 241766Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132730
GnomAD4 exome AF: 0.0000760 AC: 111AN: 1459782Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 726226
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
not specified Uncertain:1
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
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Atrial septal defect 7 Benign:1
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Cardiovascular phenotype Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at