NM_015512.5:c.4987C>T

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.4987C>T(p.Arg1663Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,448 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1663G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 58 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.02

Publications

6 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=0.0060506463).

BP6

Variant 3-52362394-C-T is Benign according to our data. Variant chr3-52362394-C-T is described in ClinVar as Benign. ClinVar VariationId is 478453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00286 (435/152342) while in subpopulation EAS AF = 0.02 (104/5188). AF 95% confidence interval is 0.0169. There are 4 homozygotes in GnomAd4. There are 216 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.4987C>T	p.Arg1663Cys	missense_variant	Exon 31 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.4987C>T	p.Arg1663Cys	missense_variant	Exon 32 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.4987C>T	p.Arg1663Cys	missense_variant	Exon 32 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.4987C>T	p.Arg1663Cys	missense_variant	Exon 32 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 link	c.4987C>T	p.Arg1663Cys	missense_variant	Exon 31 of 78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000466628.1 link	n.141C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5
DNAH1	ENST00000486752.5 link	n.5248C>T		non_coding_transcript_exon_variant	Exon 31 of 77	2

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

431

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0198

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00763

AC:

1894

AN:

248154

AF XY:

0.00602

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.0431

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.00547

GnomAD4 exome

AF:

0.00212

AC:

3091

AN:

1461106

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1404

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.000837

AC:

AN:

33472

American (AMR)

AF:

0.0391

AC:

1746

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26120

East Asian (EAS)

AF:

0.0223

AC:

884

AN:

39684

South Asian (SAS)

AF:

0.000476

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000235

AC:

261

AN:

1111670

Other (OTH)

AF:

0.00171

AC:

103

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

160

320

480

640

800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00286

AC:

435

AN:

152342

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41572

American (AMR)

AF:

0.0159

AC:

244

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0200

AC:

104

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68030

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

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:

0.00225

Hom.:

Bravo

AF:

0.00499

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.000469

AC:

ExAC

AF:

0.00609

AC:

738

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.97

PhyloP100

2.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.2

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Vest4

0.60

MVP

0.44

MPC

0.36

ClinPred

0.041

GERP RS

5.7

gMVP

0.86

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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