rs45461493

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.5171G>A​(p.Gly1724Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

8
7
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH8NM_001206927.2 linkc.5171G>A p.Gly1724Asp missense_variant Exon 37 of 93 ENST00000327475.11 NP_001193856.1 Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH8ENST00000327475.11 linkc.5171G>A p.Gly1724Asp missense_variant Exon 37 of 93 5 NM_001206927.2 ENSP00000333363.7 A0A075B6F3
DNAH8ENST00000359357.7 linkc.4520G>A p.Gly1507Asp missense_variant Exon 35 of 91 2 ENSP00000352312.3 Q96JB1-1
DNAH8ENST00000449981.6 linkc.5171G>A p.Gly1724Asp missense_variant Exon 36 of 82 5 ENSP00000415331.2 H0Y7V4

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
152060
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000203
AC:
51
AN:
251048
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.000432
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000384
AC:
561
AN:
1461260
Hom.:
1
Cov.:
30
AF XY:
0.000371
AC XY:
270
AN XY:
726924
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000490
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000132
AC:
20
AN:
152060
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000224
Hom.:
0
Bravo
AF:
0.0000982
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5171G>A (p.G1724D) alteration is located in exon 37 (coding exon 36) of the DNAH8 gene. This alteration results from a G to A substitution at nucleotide position 5171, causing the glycine (G) at amino acid position 1724 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia Uncertain:1
Apr 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1724 of the DNAH8 protein (p.Gly1724Asp). This variant is present in population databases (rs45461493, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 454576). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;D;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Pathogenic
3.8
.;.;H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.3
.;D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.0010
.;D;D
Polyphen
1.0
.;.;D
Vest4
0.61
MVP
0.79
MPC
0.65
ClinPred
0.69
D
GERP RS
5.8
Varity_R
0.90
gMVP
0.74

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: rs45461493; hg19: chr6-38816549; API