5-173233371-C-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1
The ENST00000424406.2(NKX2-5):c.*126G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,536,904 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0019 ( 6 hom. )
Consequence
NKX2-5
ENST00000424406.2 3_prime_UTR
ENST00000424406.2 3_prime_UTR
Scores
1
1
12
Clinical Significance
Conservation
PhyloP100: -0.0570
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.013406545).
BP6
?
Variant 5-173233371-C-T is Benign according to our data. Variant chr5-173233371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 190833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173233371-C-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00122 (186/152100) while in subpopulation SAS AF= 0.00208 (10/4806). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.335-162G>A | intron_variant | ENST00000329198.5 | |||
NKX2-5 | NM_001166176.2 | c.428G>A | p.Arg143Gln | missense_variant | 2/2 | ||
NKX2-5 | NM_001166175.2 | c.*126G>A | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000424406.2 | c.*126G>A | 3_prime_UTR_variant | 2/2 | 1 | ||||
NKX2-5 | ENST00000329198.5 | c.335-162G>A | intron_variant | 1 | NM_004387.4 | P1 | |||
NKX2-5 | ENST00000521848.1 | c.428G>A | p.Arg143Gln | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00121 AC: 184AN: 151988Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00127 AC: 177AN: 139470Hom.: 0 AF XY: 0.00128 AC XY: 96AN XY: 74830
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GnomAD4 exome AF: 0.00192 AC: 2655AN: 1384804Hom.: 6 Cov.: 35 AF XY: 0.00194 AC XY: 1329AN XY: 683336
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GnomAD4 genome ? AF: 0.00122 AC: 186AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74366
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | NKX2-5: BP4, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2021 | This variant is associated with the following publications: (PMID: 27373559, 26334177, 25500235) - |
NKX2-5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 31, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Atrial septal defect 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
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 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Pathogenic
D
Vest4
MVP
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at