rs61734653

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1981A>G(p.Met661Val) 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 1,599,060 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: 33)

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: 1.01

Publications

4 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=0.004538268).

BP6

Variant 3-52347849-A-G is Benign according to our data. Variant chr3-52347849-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478421.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 = 0.00374 (570/152270) while in subpopulation SAS AF = 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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.1981A>G	p.Met661Val	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.1981A>G	p.Met661Val	missense	Exon 12 of 78	ENSP00000401514.2
DNAH1	ENST00000486752.5	TSL:2	n.2242A>G		non_coding_transcript_exon	Exon 12 of 77
DNAH1	ENST00000497875.1	TSL:2	n.2146A>G		non_coding_transcript_exon	Exon 13 of 21

Frequencies

GnomAD3 genomes

AF:

0.00375

AC:

571

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

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:

0.00564

AC:

1286

AN:

227936

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.000886

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00354

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00417

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00576

AC:

8328

AN:

1446790

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

4510

AN XY:

717922

show subpopulations

African (AFR)

AF:

0.000663

AC:

AN:

33182

American (AMR)

AF:

0.00229

AC:

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

25716

East Asian (EAS)

AF:

0.00371

AC:

145

AN:

39112

South Asian (SAS)

AF:

0.0232

AC:

1945

AN:

83782

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

52650

Middle Eastern (MID)

AF:

0.00506

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00510

AC:

5629

AN:

1104118

Other (OTH)

AF:

0.00569

AC:

340

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

434

869

1303

1738

2172

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:

0.00374

AC:

570

AN:

152270

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41548

American (AMR)

AF:

0.00314

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00444

AC:

AN:

5178

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4830

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00474

AC:

322

AN:

68000

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

153

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:

0.00386

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000735

AC:

ESP6500EA

AF:

0.00382

AC:

ExAC

AF:

0.00577

AC:

697

Asia WGS

AF:

0.00837

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

not provided (3)

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.4

(source)

DANN

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.066

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.96

PhyloP100

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.12

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.18

MVP

0.072

MPC

0.13

ClinPred

0.00059

GERP RS

3.1

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

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

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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