chr5-173233518-AAT-A
Variant summary
Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_004387.4(NKX2-5):c.335-311_335-310delAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 687,762 control chromosomes in the GnomAD database, including 96 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0041 ( 4 hom., cov: 19)
Exomes 𝑓: 0.0089 ( 92 hom. )
Consequence
NKX2-5
NM_004387.4 intron
NM_004387.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.455
Publications
1 publications found
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]
NKX2-5 Gene-Disease associations (from GenCC):
- atrial septal defect 7Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
- hypothyroidism, congenital, nongoitrous, 5Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- NKX2.5-related congenital, conduction and myopathic heart diseaseInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- tetralogy of fallotInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- conotruncal heart malformationsInheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- athyreosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial atrial fibrillationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial bicuspid aortic valveInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated congenital aspleniaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -16 ACMG points.
BP6
Variant 5-173233518-AAT-A is Benign according to our data. Variant chr5-173233518-AAT-A is described in ClinVar as [Likely_benign]. Clinvar id is 445633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00408 (561/137630) while in subpopulation SAS AF = 0.0177 (77/4360). AF 95% confidence interval is 0.0145. There are 4 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
BS2
High AC in GnomAd4 at 561 AD,Unknown,SD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.335-311_335-310delAT | intron_variant | Intron 1 of 1 | ENST00000329198.5 | NP_004378.1 | ||
NKX2-5 | XM_017009071.3 | c.*526_*527delAT | 3_prime_UTR_variant | Exon 2 of 2 | XP_016864560.1 | |||
NKX2-5 | NM_001166176.2 | c.335-56_335-55delAT | intron_variant | Intron 1 of 1 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.335-19_335-18delAT | intron_variant | Intron 1 of 1 | NP_001159647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.335-311_335-310delAT | intron_variant | Intron 1 of 1 | 1 | NM_004387.4 | ENSP00000327758.4 | |||
NKX2-5 | ENST00000424406.2 | c.335-19_335-18delAT | intron_variant | Intron 1 of 1 | 1 | ENSP00000395378.2 | ||||
NKX2-5 | ENST00000521848.1 | c.335-56_335-55delAT | intron_variant | Intron 1 of 1 | 2 | ENSP00000427906.1 |
Frequencies
GnomAD3 genomes AF: 0.00408 AC: 561AN: 137564Hom.: 4 Cov.: 19 show subpopulations
GnomAD3 genomes
AF:
AC:
561
AN:
137564
Hom.:
Cov.:
19
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:
GnomAD2 exomes AF: 0.0128 AC: 1210AN: 94176 AF XY: 0.0128 show subpopulations
GnomAD2 exomes
AF:
AC:
1210
AN:
94176
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00890 AC: 4898AN: 550132Hom.: 92 AF XY: 0.00915 AC XY: 2644AN XY: 288838 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4898
AN:
550132
Hom.:
AF XY:
AC XY:
2644
AN XY:
288838
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
470
AN:
9952
American (AMR)
AF:
AC:
165
AN:
22904
Ashkenazi Jewish (ASJ)
AF:
AC:
317
AN:
16710
East Asian (EAS)
AF:
AC:
60
AN:
28826
South Asian (SAS)
AF:
AC:
797
AN:
42266
European-Finnish (FIN)
AF:
AC:
240
AN:
23628
Middle Eastern (MID)
AF:
AC:
26
AN:
2190
European-Non Finnish (NFE)
AF:
AC:
2530
AN:
376520
Other (OTH)
AF:
AC:
293
AN:
27136
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.318
Heterozygous variant carriers
0
372
744
1116
1488
1860
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome AF: 0.00408 AC: 561AN: 137630Hom.: 4 Cov.: 19 AF XY: 0.00398 AC XY: 267AN XY: 67146 show subpopulations
GnomAD4 genome
AF:
AC:
561
AN:
137630
Hom.:
Cov.:
19
AF XY:
AC XY:
267
AN XY:
67146
show subpopulations
African (AFR)
AF:
AC:
88
AN:
35728
American (AMR)
AF:
AC:
53
AN:
14130
Ashkenazi Jewish (ASJ)
AF:
AC:
55
AN:
3258
East Asian (EAS)
AF:
AC:
1
AN:
4822
South Asian (SAS)
AF:
AC:
77
AN:
4360
European-Finnish (FIN)
AF:
AC:
13
AN:
8850
Middle Eastern (MID)
AF:
AC:
4
AN:
264
European-Non Finnish (NFE)
AF:
AC:
257
AN:
63438
Other (OTH)
AF:
AC:
6
AN:
1906
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
26
51
77
102
128
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
May 30, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Aug 10, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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