chr5-13793948-C-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001369.3(DNAH5):c.7998G>T(p.Glu2666Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,962 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. E2666E) 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 -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.7998G>T | p.Glu2666Asp | missense_variant | 48/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.7998G>T | p.Glu2666Asp | missense_variant | 48/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.7953G>T | p.Glu2651Asp | missense_variant | 48/79 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00137 AC: 209AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00122 AC: 307AN: 250870Hom.: 2 AF XY: 0.00121 AC XY: 164AN XY: 135564
GnomAD4 exome AF: 0.00234 AC: 3424AN: 1461676Hom.: 16 Cov.: 32 AF XY: 0.00235 AC XY: 1708AN XY: 727156
GnomAD4 genome ? AF: 0.00137 AC: 208AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94AN XY: 74466
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 06, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Primary ciliary dyskinesia Benign:3
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2016 | The E2666D variant in the DNAH5 gene has been reported previously in the heterozygous state in one individual with idiopathic, non-syndromic reduced sperm motility (Zuccarello et al., 2008). While not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports E2666D was observed in 22/8600 (0.25%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The E2666D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E2666D as a variant of uncertain significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Glu2666Asp va riant in DNAH5 has been reported in 1 heterozygous Caucasian individual with iso lated asthenozoospermia (Zuccarello 2008). It has also been identified in 0.2% ( 115/66240) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs148720124). Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, while the clinical significance of the p.Glu2666As p variant is uncertain, its frequency suggests that it is more likely to be beni gn. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at