NM_001369.3:c.13569C>A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_001369.3(DNAH5):c.13569C>A(p.Asp4523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D4523D) has been classified as Likely benign.
Frequency
Consequence
NM_001369.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DNAH5 | ENST00000265104.5 | c.13569C>A | p.Asp4523Glu | missense_variant | Exon 78 of 79 | 1 | NM_001369.3 | ENSP00000265104.4 | ||
DNAH5 | ENST00000681290.1 | c.13524C>A | p.Asp4508Glu | missense_variant | Exon 78 of 79 | ENSP00000505288.1 | ||||
DNAH5 | ENST00000683611.1 | n.902C>A | non_coding_transcript_exon_variant | Exon 4 of 5 |
Frequencies
GnomAD3 genomes AF: 0.000822 AC: 125AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000382 AC: 96AN: 251334Hom.: 0 AF XY: 0.000375 AC XY: 51AN XY: 135828
GnomAD4 exome AF: 0.000198 AC: 289AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 145AN XY: 727234
GnomAD4 genome AF: 0.000821 AC: 125AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57AN XY: 74422
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Uncertain:4
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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Primary ciliary dyskinesia Uncertain:1Benign:2
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. -
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not specified Benign:2
Asp4523Glu in exon 78 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (15/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs151080414). -
Variant summary: DNAH5 c.13569C>A (p.Asp4523Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251334 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in DNAH5 causing Primary ciliary dyskinesia 3 phenotype. To our knowledge, no occurrence of c.13569C>A in individuals affected with Primary ciliary dyskinesia 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 163131). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at