3-52351976-A-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.2744A>G(p.Asn915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,602,576 control chromosomes in the GnomAD database, including 69 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 (★★).

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 65 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.489

Publications

5 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=0.007988453).

BP6

Variant 3-52351976-A-G is Benign according to our data. Variant chr3-52351976-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478434.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 = 0.00375 (571/152342) while in subpopulation SAS AF = 0.0232 (112/4828). AF 95% confidence interval is 0.0197. There are 4 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.2744A>G	p.Asn915Ser	missense_variant	Exon 17 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.2744A>G	p.Asn915Ser	missense_variant	Exon 18 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.2744A>G	p.Asn915Ser	missense_variant	Exon 18 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.2744A>G	p.Asn915Ser	missense_variant	Exon 18 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 link	c.2744A>G	p.Asn915Ser	missense_variant	Exon 17 of 78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5 link	n.3005A>G		non_coding_transcript_exon_variant	Exon 17 of 77	2
DNAH1	ENST00000497875.1 link	n.2909A>G		non_coding_transcript_exon_variant	Exon 18 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00555

AC:

1283

AN:

231132

AF XY:

0.00655

show subpopulations

Gnomad AFR exome

AF:

0.000888

Gnomad AMR exome

AF:

0.00245

Gnomad ASJ exome

AF:

0.00166

Gnomad EAS exome

AF:

0.00349

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00575

AC:

8342

AN:

1450234

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

4513

AN XY:

720002

show subpopulations

African (AFR)

AF:

0.000663

AC:

AN:

33206

American (AMR)

AF:

0.00227

AC:

AN:

43194

Ashkenazi Jewish (ASJ)

AF:

0.00162

AC:

AN:

25858

East Asian (EAS)

AF:

0.00372

AC:

146

AN:

39270

South Asian (SAS)

AF:

0.0233

AC:

1946

AN:

83572

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

52676

Middle Eastern (MID)

AF:

0.00532

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00509

AC:

5639

AN:

1106836

Other (OTH)

AF:

0.00565

AC:

339

AN:

59988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

438

875

1313

1750

2188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00375

AC:

571

AN:

152342

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41582

American (AMR)

AF:

0.00314

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00444

AC:

AN:

5182

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4828

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00473

AC:

322

AN:

68034

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00400

Hom.:

Bravo

AF:

0.00291

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000750

AC:

ESP6500EA

AF:

0.00371

AC:

ExAC

AF:

0.00564

AC:

681

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.98

PhyloP100

0.49

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.39

REVEL

Benign

0.082

Sift

Benign

0.49

Sift4G

Benign

0.42

Vest4

0.19

MVP

0.19

MPC

0.098

ClinPred

0.0058

GERP RS

4.4

gMVP

0.40

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over