rs374917069

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001369.3(DNAH5):​c.4797-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00003305
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.229
Variant links:
Genes affected
DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 5-13859612-T-C is Benign according to our data. Variant chr5-13859612-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAH5NM_001369.3 linkuse as main transcriptc.4797-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000265104.5 NP_001360.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAH5ENST00000265104.5 linkuse as main transcriptc.4797-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_001369.3 ENSP00000265104 P4
DNAH5ENST00000681290.1 linkuse as main transcriptc.4752-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENSP00000505288 A1

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251284
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135802
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000131
AC:
191
AN:
1461188
Hom.:
0
Cov.:
31
AF XY:
0.000124
AC XY:
90
AN XY:
726930
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000166
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.000144
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Primary ciliary dyskinesia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
4.0
DANN
Benign
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000033
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374917069; hg19: chr5-13859721; API