rs419752

Positions:

chr3-52395649-C-T

Variant summary

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

The NM_015512.5(DNAH1):c.11230C>T(p.Arg3744Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0445 in 1,613,794 control chromosomes in the GnomAD database, including 1,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 145 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1630 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.64

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=0.0059680045).

BP6

Variant 3-52395649-C-T is Benign according to our data. Variant chr3-52395649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52395649-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.038 (5786/152332) while in subpopulation NFE AF= 0.0494 (3363/68024). AF 95% confidence interval is 0.048. There are 145 homozygotes in gnomad4. There are 2660 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 145 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAH1	NM_015512.5 linkuse as main transcript	c.11230C>T	p.Arg3744Cys	missense_variant	70/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 linkuse as main transcript	c.11299C>T	p.Arg3767Cys	missense_variant	72/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.11230C>T	p.Arg3744Cys	missense_variant	71/79		XP_016861619.1
DNAH1	XM_017006131.2 linkuse as main transcript	c.11173C>T	p.Arg3725Cys	missense_variant	71/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.11230C>T	p.Arg3744Cys	missense_variant	70/78	1	NM_015512.5	ENSP00000401514	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.11687C>T		non_coding_transcript_exon_variant	69/77	2
DNAH1	ENST00000488988.5 linkuse as main transcript	n.3016C>T		non_coding_transcript_exon_variant	17/25	2
DNAH1	ENST00000490713.5 linkuse as main transcript	c.1930C>T	p.Arg644Cys	missense_variant, NMD_transcript_variant	13/20	5		ENSP00000419071

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

5785

AN:

152214

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.0214

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0439

GnomAD3 exomes

AF:

0.0372

AC:

9249

AN:

248514

Hom.:

215

AF XY:

0.0375

AC XY:

5058

AN XY:

134982

show subpopulations

Gnomad AFR exome

AF:

0.0220

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.0287

Gnomad EAS exome

AF:

0.0180

Gnomad SAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.0323

Gnomad NFE exome

AF:

0.0496

Gnomad OTH exome

AF:

0.0470

GnomAD4 exome

AF:

0.0451

AC:

65969

AN:

1461462

Hom.:

1630

Cov.:

AF XY:

0.0447

AC XY:

32532

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.0364

Gnomad4 ASJ exome

AF:

0.0297

Gnomad4 EAS exome

AF:

0.0166

Gnomad4 SAS exome

AF:

0.0197

Gnomad4 FIN exome

AF:

0.0332

Gnomad4 NFE exome

AF:

0.0501

Gnomad4 OTH exome

AF:

0.0464

GnomAD4 genome

AF:

0.0380

AC:

5786

AN:

152332

Hom.:

145

Cov.:

AF XY:

0.0357

AC XY:

2660

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0207

Gnomad4 AMR

AF:

0.0484

Gnomad4 ASJ

AF:

0.0300

Gnomad4 EAS

AF:

0.0210

Gnomad4 SAS

AF:

0.0211

Gnomad4 FIN

AF:

0.0299

Gnomad4 NFE

AF:

0.0494

Gnomad4 OTH

AF:

0.0458

Alfa

AF:

0.0484

Hom.:

435

Bravo

AF:

0.0395

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.0230

AC:

ESP6500EA

AF:

0.0474

AC:

403

ExAC

AF:

0.0366

AC:

4436

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.0501

EpiControl

AF:

0.0540

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.4

REVEL

Benign

0.24

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Vest4

0.23

MPC

0.41

ClinPred

0.037

GERP RS

3.2

gMVP

0.68

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