NM_015512.5:c.9326G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015512.5(DNAH1):c.9326G>C(p.Cys3109Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,612,522 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C3109R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64

Publications

0 publications found

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]

DNAH1 Gene-Disease associations (from GenCC):

spermatogenic failure 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
ciliary dyskinesia, primary, 37
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40785283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAH1	NM_015512.5 link	c.9326G>C	p.Cys3109Ser	missense_variant	Exon 58 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 link	c.9395G>C	p.Cys3132Ser	missense_variant	Exon 60 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.9326G>C	p.Cys3109Ser	missense_variant	Exon 59 of 79		XP_016861619.1
DNAH1	XM_017006131.2 link	c.9395G>C	p.Cys3132Ser	missense_variant	Exon 60 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DNAH1	ENST00000420323.7 link	c.9326G>C	p.Cys3109Ser	missense_variant	Exon 58 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5 link	n.9587G>C		non_coding_transcript_exon_variant	Exon 58 of 77	2
DNAH1	ENST00000488988.5 link	n.916G>C		non_coding_transcript_exon_variant	Exon 6 of 25	2
DNAH1	ENST00000490713.5 link	n.26G>C		non_coding_transcript_exon_variant	Exon 1 of 20	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000569

AC:

AN:

245916

AF XY:

0.0000524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000729

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460150

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726298

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.000302

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111466

Other (OTH)

AF:

0.0000829

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000660

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine with serine at codon 3109 of the DNAH1 protein (p.Cys3109Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs775151697, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. 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: "Benign"; 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

0.31

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Benign

-0.087

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.021

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.87

PhyloP100

4.6

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.32

Sift

Benign

0.77

Sift4G

Benign

0.51

Vest4

0.80

MutPred

0.53

Gain of disorder (P = 0.0379);

MVP

0.50

MPC

0.18

ClinPred

0.079

GERP RS

5.2

PromoterAI

0.0018

Neutral

(source)

gMVP

0.23

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over