rs61734638

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000420323.7(DNAH1):c.4531G>A(p.Val1511Met) variant causes a missense change. The variant allele was found at a frequency of 0.0253 in 1,613,938 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 33)

Exomes 𝑓: 0.026 ( 578 hom. )

Consequence

DNAH1
ENST00000420323.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004373938).

BP6

Variant 3-52360039-G-A is Benign according to our data. Variant chr3-52360039-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52360039-G-A is described in Lovd as [Pathogenic]. Variant chr3-52360039-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2738/152372) while in subpopulation NFE AF= 0.0286 (1943/68032). AF 95% confidence interval is 0.0275. There are 41 homozygotes in gnomad4. There are 1245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAH1	NM_015512.5 linkuse as main transcript	c.4531G>A	p.Val1511Met	missense_variant	27/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 linkuse as main transcript	c.4531G>A	p.Val1511Met	missense_variant	28/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.4531G>A	p.Val1511Met	missense_variant	28/79		XP_016861619.1
DNAH1	XM_017006131.2 linkuse as main transcript	c.4531G>A	p.Val1511Met	missense_variant	28/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.4531G>A	p.Val1511Met	missense_variant	27/78	1	NM_015512.5	ENSP00000401514	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.4792G>A		non_coding_transcript_exon_variant	27/77	2

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2736

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00598

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0286

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0186

AC:

4632

AN:

248978

Hom.:

AF XY:

0.0190

AC XY:

2572

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.00942

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0261

AC:

38164

AN:

1461566

Hom.:

578

Cov.:

AF XY:

0.0258

AC XY:

18784

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00406

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.0222

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0128

Gnomad4 FIN exome

AF:

0.00984

Gnomad4 NFE exome

AF:

0.0305

Gnomad4 OTH exome

AF:

0.0211

GnomAD4 genome

AF:

0.0180

AC:

2738

AN:

152372

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1245

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00596

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.00734

Gnomad4 NFE

AF:

0.0286

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0244

Hom.:

Bravo

AF:

0.0183

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.00627

AC:

ESP6500EA

AF:

0.0291

AC:

248

ExAC

AF:

0.0188

AC:

2284

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628, 29449551) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DNAH1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.37

MutationTaster

Benign

0.98

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.20

MPC

0.53

ClinPred

0.051

GERP RS

4.2

gMVP

0.64

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over