rs369714206

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_001369.3(DNAH5):ā€‹c.13174T>Cā€‹(p.Phe4392Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00023 ( 0 hom., cov: 32)
Exomes š‘“: 0.000026 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

8
4
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 9.27
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.779
BP6
Variant 5-13708287-A-G is Benign according to our data. Variant chr5-13708287-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407243.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAH5NM_001369.3 linkuse as main transcriptc.13174T>C p.Phe4392Leu missense_variant 76/79 ENST00000265104.5 NP_001360.1 Q8TE73

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAH5ENST00000265104.5 linkuse as main transcriptc.13174T>C p.Phe4392Leu missense_variant 76/791 NM_001369.3 ENSP00000265104.4 Q8TE73
DNAH5ENST00000681290.1 linkuse as main transcriptc.13129T>C p.Phe4377Leu missense_variant 76/79 ENSP00000505288.1 A0A7P0Z455
DNAH5ENST00000683611.1 linkuse as main transcriptn.507T>C non_coding_transcript_exon_variant 2/5

Frequencies

GnomAD3 genomes
AF:
0.000223
AC:
34
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000652
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251348
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.000615
Gnomad AMR exome
AF:
0.0000578
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:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461870
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000717
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.000674
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000152
Hom.:
0
Bravo
AF:
0.000242
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2024The c.13174T>C (p.F4392L) alteration is located in exon 76 (coding exon 76) of the DNAH5 gene. This alteration results from a T to C substitution at nucleotide position 13174, causing the phenylalanine (F) at amino acid position 4392 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Benign
-0.94
T
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.67
Gain of helix (P = 0.0325);
MVP
0.47
MPC
0.25
ClinPred
0.56
D
GERP RS
5.2
Varity_R
0.89
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs369714206; hg19: chr5-13708396; API