chr3-52347837-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015512.5(DNAH1):c.1969C>G(p.Pro657Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,593,138 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 17 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.47

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010119915).

BP6

Variant 3-52347837-C-G is Benign according to our data. Variant chr3-52347837-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 544643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000322 (49/152316) while in subpopulation SAS AF = 0.00911 (44/4828). AF 95% confidence interval is 0.00698. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.1969C>G	p.Pro657Ala	missense	Exon 12 of 78	NP_056327.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.1969C>G	p.Pro657Ala	missense	Exon 12 of 78	ENSP00000401514.2
DNAH1	ENST00000486752.5	TSL:2	n.2230C>G		non_coding_transcript_exon	Exon 12 of 77
DNAH1	ENST00000497875.1	TSL:2	n.2134C>G		non_coding_transcript_exon	Exon 13 of 21

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00126

AC:

282

AN:

223032

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0000754

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.000896

GnomAD4 exome

AF:

0.000633

AC:

912

AN:

1440822

Hom.:

Cov.:

AF XY:

0.000883

AC XY:

631

AN XY:

714210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33042

American (AMR)

AF:

0.00

AC:

AN:

42008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25566

East Asian (EAS)

AF:

0.00

AC:

AN:

38828

South Asian (SAS)

AF:

0.0101

AC:

839

AN:

83088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52408

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000545

AC:

AN:

1100672

Other (OTH)

AF:

0.000874

AC:

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000322

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00144

AC:

174

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

PhyloP100

3.5

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.17

Sift

Benign

0.083

Sift4G

Benign

0.097

Vest4

0.45

MVP

0.25

MPC

0.13

ClinPred

0.13

GERP RS

4.1

gMVP

0.60

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over