rs370624357

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015512.5(DNAH1):​c.11360G>A​(p.Arg3787His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,602,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

1
6
10

Clinical Significance

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

Conservation

PhyloP100: 3.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29627347).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAH1NM_015512.5 linkuse as main transcriptc.11360G>A p.Arg3787His missense_variant 71/78 ENST00000420323.7 NP_056327.4 Q9P2D7-4A0A140VJI6
DNAH1XM_017006129.2 linkuse as main transcriptc.11429G>A p.Arg3810His missense_variant 73/80 XP_016861618.1
DNAH1XM_017006130.2 linkuse as main transcriptc.11360G>A p.Arg3787His missense_variant 72/79 XP_016861619.1 Q9P2D7-4A0A140VJI6
DNAH1XM_017006131.2 linkuse as main transcriptc.11303G>A p.Arg3768His missense_variant 72/79 XP_016861620.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAH1ENST00000420323.7 linkuse as main transcriptc.11360G>A p.Arg3787His missense_variant 71/781 NM_015512.5 ENSP00000401514.2 Q9P2D7-4
DNAH1ENST00000486752.5 linkuse as main transcriptn.11817G>A non_coding_transcript_exon_variant 70/772
DNAH1ENST00000488988.5 linkuse as main transcriptn.3146G>A non_coding_transcript_exon_variant 18/252
DNAH1ENST00000490713.5 linkuse as main transcriptn.2060G>A non_coding_transcript_exon_variant 14/205 ENSP00000419071.1 H7C563

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000677
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
GnomAD3 exomes
AF:
0.0000829
AC:
19
AN:
229104
Hom.:
0
AF XY:
0.0000965
AC XY:
12
AN XY:
124378
show subpopulations
Gnomad AFR exome
AF:
0.00105
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000106
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000194
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000338
AC:
49
AN:
1450388
Hom.:
0
Cov.:
31
AF XY:
0.0000319
AC XY:
23
AN XY:
720496
show subpopulations
Gnomad4 AFR exome
AF:
0.000962
Gnomad4 AMR exome
AF:
0.0000465
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000712
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000542
Gnomad4 OTH exome
AF:
0.0000500
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.000677
Gnomad4 AMR
AF:
0.0000655
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:
0.00
Alfa
AF:
0.000315
Hom.:
0
Bravo
AF:
0.000234
ESP6500AA
AF:
0.000235
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000124
AC:
15

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 27, 2024The c.11360G>A (p.R3787H) alteration is located in exon 71 (coding exon 70) of the DNAH1 gene. This alteration results from a G to A substitution at nucleotide position 11360, causing the arginine (R) at amino acid position 3787 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 20, 2022This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3787 of the DNAH1 protein (p.Arg3787His). This variant is present in population databases (rs370624357, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 478397). 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: "Probably Damaging"; 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
Benign
0.12
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
23
DANN
Pathogenic
1.0
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.30
T
MetaSVM
Benign
-0.92
T
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.8
D
REVEL
Benign
0.19
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.014
D
Vest4
0.61
MVP
0.52
MPC
0.62
ClinPred
0.45
T
GERP RS
4.3
gMVP
0.55

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: rs370624357; hg19: chr3-52430484; COSMIC: COSV99963597; COSMIC: COSV99963597; API