rs200450328

Variant summary

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

The NM_015512.5(DNAH1):​c.888G>C​(p.Gln296His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,597,516 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q296R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 3 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

17

Clinical Significance

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

Conservation

PhyloP100: -1.05
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005332947).
BP6
Variant 3-52331164-G-C is Benign according to our data. Variant chr3-52331164-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 478507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00039 (563/1445142) while in subpopulation SAS AF= 0.00241 (201/83290). AF 95% confidence interval is 0.00214. There are 3 homozygotes in gnomad4_exome. There are 320 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH1NM_015512.5 linkc.888G>C p.Gln296His missense_variant Exon 7 of 78 ENST00000420323.7 NP_056327.4 Q9P2D7-4A0A140VJI6
DNAH1XM_017006129.2 linkc.888G>C p.Gln296His missense_variant Exon 8 of 80 XP_016861618.1
DNAH1XM_017006130.2 linkc.888G>C p.Gln296His missense_variant Exon 8 of 79 XP_016861619.1 Q9P2D7-4A0A140VJI6
DNAH1XM_017006131.2 linkc.888G>C p.Gln296His missense_variant Exon 8 of 79 XP_016861620.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH1ENST00000420323.7 linkc.888G>C p.Gln296His missense_variant Exon 7 of 78 1 NM_015512.5 ENSP00000401514.2 Q9P2D7-4
DNAH1ENST00000486752.5 linkn.1149G>C non_coding_transcript_exon_variant Exon 7 of 77 2
DNAH1ENST00000497875.1 linkn.1053G>C non_coding_transcript_exon_variant Exon 8 of 21 2

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152256
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00432
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000672
AC:
149
AN:
221566
Hom.:
2
AF XY:
0.000844
AC XY:
101
AN XY:
119708
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.000286
Gnomad ASJ exome
AF:
0.00242
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00268
Gnomad FIN exome
AF:
0.0000512
Gnomad NFE exome
AF:
0.000354
Gnomad OTH exome
AF:
0.00109
GnomAD4 exome
AF:
0.000390
AC:
563
AN:
1445142
Hom.:
3
Cov.:
31
AF XY:
0.000446
AC XY:
320
AN XY:
717046
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.000262
Gnomad4 ASJ exome
AF:
0.00244
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00241
Gnomad4 FIN exome
AF:
0.0000573
Gnomad4 NFE exome
AF:
0.000209
Gnomad4 OTH exome
AF:
0.000719
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152374
Hom.:
0
Cov.:
32
AF XY:
0.000443
AC XY:
33
AN XY:
74524
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00432
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000526
Hom.:
0
Bravo
AF:
0.000351
ESP6500AA
AF:
0.000253
AC:
1
ESP6500EA
AF:
0.000361
AC:
3
ExAC
AF:
0.000646
AC:
78
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

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

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1
Jan 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Feb 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DNAH1: BP4, BS2 -

DNAH1-related disorder Benign:1
Aug 09, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
9.3
DANN
Benign
0.89
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.087
N
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.0053
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.65
N
REVEL
Benign
0.035
Sift
Benign
0.15
T
Sift4G
Benign
0.17
T
Vest4
0.096
MutPred
0.26
Loss of methylation at K301 (P = 0.0977);
MVP
0.072
MPC
0.12
ClinPred
0.0011
T
GERP RS
1.8
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs200450328; hg19: chr3-52365180; API