rs419752

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015512.5(DNAH1):​c.11230C>T​(p.Arg3744Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0445 in 1,613,794 control chromosomes in the GnomAD database, including 1,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 145 hom., cov: 32)
Exomes 𝑓: 0.045 ( 1630 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

2
7
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.64
Variant links:
Genes affected
DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0059680045).
BP6
Variant 3-52395649-C-T is Benign according to our data. Variant chr3-52395649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52395649-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.038 (5786/152332) while in subpopulation NFE AF= 0.0494 (3363/68024). AF 95% confidence interval is 0.048. There are 145 homozygotes in gnomad4. There are 2660 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 145 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAH1NM_015512.5 linkuse as main transcriptc.11230C>T p.Arg3744Cys missense_variant 70/78 ENST00000420323.7
DNAH1XM_017006129.2 linkuse as main transcriptc.11299C>T p.Arg3767Cys missense_variant 72/80
DNAH1XM_017006130.2 linkuse as main transcriptc.11230C>T p.Arg3744Cys missense_variant 71/79
DNAH1XM_017006131.2 linkuse as main transcriptc.11173C>T p.Arg3725Cys missense_variant 71/79

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAH1ENST00000420323.7 linkuse as main transcriptc.11230C>T p.Arg3744Cys missense_variant 70/781 NM_015512.5 P1Q9P2D7-4
DNAH1ENST00000486752.5 linkuse as main transcriptn.11687C>T non_coding_transcript_exon_variant 69/772
DNAH1ENST00000488988.5 linkuse as main transcriptn.3016C>T non_coding_transcript_exon_variant 17/252
DNAH1ENST00000490713.5 linkuse as main transcriptc.1930C>T p.Arg644Cys missense_variant, NMD_transcript_variant 13/205

Frequencies

GnomAD3 genomes
AF:
0.0380
AC:
5785
AN:
152214
Hom.:
144
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0208
Gnomad AMI
AF:
0.0868
Gnomad AMR
AF:
0.0484
Gnomad ASJ
AF:
0.0300
Gnomad EAS
AF:
0.0214
Gnomad SAS
AF:
0.0213
Gnomad FIN
AF:
0.0299
Gnomad MID
AF:
0.0380
Gnomad NFE
AF:
0.0494
Gnomad OTH
AF:
0.0439
GnomAD3 exomes
AF:
0.0372
AC:
9249
AN:
248514
Hom.:
215
AF XY:
0.0375
AC XY:
5058
AN XY:
134982
show subpopulations
Gnomad AFR exome
AF:
0.0220
Gnomad AMR exome
AF:
0.0335
Gnomad ASJ exome
AF:
0.0287
Gnomad EAS exome
AF:
0.0180
Gnomad SAS exome
AF:
0.0193
Gnomad FIN exome
AF:
0.0323
Gnomad NFE exome
AF:
0.0496
Gnomad OTH exome
AF:
0.0470
GnomAD4 exome
AF:
0.0451
AC:
65969
AN:
1461462
Hom.:
1630
Cov.:
33
AF XY:
0.0447
AC XY:
32532
AN XY:
727024
show subpopulations
Gnomad4 AFR exome
AF:
0.0230
Gnomad4 AMR exome
AF:
0.0364
Gnomad4 ASJ exome
AF:
0.0297
Gnomad4 EAS exome
AF:
0.0166
Gnomad4 SAS exome
AF:
0.0197
Gnomad4 FIN exome
AF:
0.0332
Gnomad4 NFE exome
AF:
0.0501
Gnomad4 OTH exome
AF:
0.0464
GnomAD4 genome
AF:
0.0380
AC:
5786
AN:
152332
Hom.:
145
Cov.:
32
AF XY:
0.0357
AC XY:
2660
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0207
Gnomad4 AMR
AF:
0.0484
Gnomad4 ASJ
AF:
0.0300
Gnomad4 EAS
AF:
0.0210
Gnomad4 SAS
AF:
0.0211
Gnomad4 FIN
AF:
0.0299
Gnomad4 NFE
AF:
0.0494
Gnomad4 OTH
AF:
0.0458
Alfa
AF:
0.0484
Hom.:
435
Bravo
AF:
0.0395
TwinsUK
AF:
0.0512
AC:
190
ALSPAC
AF:
0.0467
AC:
180
ESP6500AA
AF:
0.0230
AC:
97
ESP6500EA
AF:
0.0474
AC:
403
ExAC
AF:
0.0366
AC:
4436
Asia WGS
AF:
0.0350
AC:
122
AN:
3478
EpiCase
AF:
0.0501
EpiControl
AF:
0.0540

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 09, 2018This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.37
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D
MetaRNN
Benign
0.0060
T
MetaSVM
Benign
-1.2
T
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-6.4
D
REVEL
Benign
0.24
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0080
D
Vest4
0.23
MPC
0.41
ClinPred
0.037
T
GERP RS
3.2
gMVP
0.68

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: rs419752; hg19: chr3-52429665; API