dbSNP rs1546737: DNAH1:p.His2319His (chr3-52373025-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015512.5(DNAH1):c.6957C>T(p.His2319His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,612,634 control chromosomes in the GnomAD database, including 75,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5629 hom., cov: 33)

Exomes 𝑓: 0.30 ( 69995 hom. )

Consequence

DNAH1
NM_015512.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.509

Publications

33 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 3-52373025-C-T is Benign according to our data. Variant chr3-52373025-C-T is described in ClinVar as Benign. ClinVar VariationId is 402601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.509 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

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.6957C>T	p.His2319His	synonymous	Exon 44 of 78	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.6957C>T	p.His2319His	synonymous	Exon 44 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.7218C>T		non_coding_transcript_exon	Exon 44 of 77

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36927

AN:

152112

Hom.:

5630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.327

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.287

AC:

71059

AN:

247388

AF XY:

0.293

show subpopulations

Gnomad AFR exome

AF:

0.0516

Gnomad AMR exome

AF:

0.250

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.362

Gnomad NFE exome

AF:

0.335

Gnomad OTH exome

AF:

0.307

GnomAD4 exome

AF:

0.305

AC:

445084

AN:

1460404

Hom.:

69995

Cov.:

AF XY:

0.305

AC XY:

221469

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.0447

AC:

1497

AN:

33466

American (AMR)

AF:

0.252

AC:

11247

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

9688

AN:

26124

East Asian (EAS)

AF:

0.259

AC:

10263

AN:

39682

South Asian (SAS)

AF:

0.256

AC:

22083

AN:

86228

European-Finnish (FIN)

AF:

0.360

AC:

18914

AN:

52594

Middle Eastern (MID)

AF:

0.318

AC:

1831

AN:

5762

European-Non Finnish (NFE)

AF:

0.317

AC:

352508

AN:

1111552

Other (OTH)

AF:

0.283

AC:

17053

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

17539

35079

52618

70158

87697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11158

22316

33474

44632

55790

<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:

0.243

AC:

36930

AN:

152230

Hom.:

5629

Cov.:

AF XY:

0.244

AC XY:

18168

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0592

AC:

2462

AN:

41586

American (AMR)

AF:

0.266

AC:

4066

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1256

AN:

3472

East Asian (EAS)

AF:

0.185

AC:

959

AN:

5182

South Asian (SAS)

AF:

0.265

AC:

1276

AN:

4824

European-Finnish (FIN)

AF:

0.352

AC:

3720

AN:

10574

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.327

AC:

22255

AN:

67980

Other (OTH)

AF:

0.256

AC:

541

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1383

2765

4148

5530

6913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.299

Hom.:

11734

Bravo

AF:

0.224

Asia WGS

AF:

0.236

AC:

821

AN:

3478

EpiCase

AF:

0.332

EpiControl

AF:

0.330

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

4.5

(source)

DANN

Benign

0.92

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over