chr3-52386735-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_015512.5(DNAH1):c.8885A>C(p.Lys2962Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,589,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.30

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: Labcorp Genetics (formerly Invitae), ClinGen
ciliary dyskinesia, primary, 37
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07671729).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000383 (550/1437522) while in subpopulation MID AF = 0.00696 (40/5744). AF 95% confidence interval is 0.00526. There are 1 homozygotes in GnomAdExome4. There are 271 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.8885A>C	p.Lys2962Thr	missense	Exon 56 of 78	NP_056327.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.8885A>C	p.Lys2962Thr	missense	Exon 56 of 78	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5	TSL:2	n.9146A>C		non_coding_transcript_exon	Exon 56 of 77
DNAH1	ENST00000488988.5	TSL:2	n.475A>C		non_coding_transcript_exon	Exon 4 of 25

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000432

AC:

AN:

205990

AF XY:

0.000449

show subpopulations

Gnomad AFR exome

AF:

0.0000880

Gnomad AMR exome

AF:

0.000671

Gnomad ASJ exome

AF:

0.00175

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000157

Gnomad NFE exome

AF:

0.000420

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000383

AC:

550

AN:

1437522

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

271

AN XY:

712656

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

32930

American (AMR)

AF:

0.000755

AC:

AN:

41050

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

25604

East Asian (EAS)

AF:

0.00

AC:

AN:

38518

South Asian (SAS)

AF:

0.000146

AC:

AN:

82076

European-Finnish (FIN)

AF:

0.0000388

AC:

AN:

51602

Middle Eastern (MID)

AF:

0.00696

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000298

AC:

328

AN:

1100444

Other (OTH)

AF:

0.000856

AC:

AN:

59554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

126

158

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:

0.000473

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41576

American (AMR)

AF:

0.00170

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68020

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000459

Hom.:

Bravo

AF:

0.000661

ESP6500AA

AF:

0.000513

AC:

ESP6500EA

AF:

0.000846

AC:

ExAC

AF:

0.000457

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Ciliary dyskinesia, primary, 37 (1)

DNAH1-related disorder (1)

Spermatogenic failure 18 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.077

MetaSVM

Uncertain

0.35

PhyloP100

7.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

Sift4G

Benign

0.076

Vest4

0.50

MVP

0.62

MPC

0.60

ClinPred

0.10

GERP RS

4.2

gMVP

0.70

Mutation Taster

=51/49

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

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

Computational scores

Splicing

Publications

Other links and lift over