rs114919804

Positions:

chr3-52391486-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.9935C>T(p.Thr3312Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,613,122 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.52

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=0.007929087).

BP6

Variant 3-52391486-C-T is Benign according to our data. Variant chr3-52391486-C-T is described in ClinVar as [Benign]. Clinvar id is 544657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00381 (579/152142) while in subpopulation AFR AF= 0.0133 (552/41490). AF 95% confidence interval is 0.0124. There are 4 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAH1	NM_015512.5 linkuse as main transcript	c.9935C>T	p.Thr3312Met	missense_variant	63/78	ENST00000420323.7
DNAH1	XM_017006129.2 linkuse as main transcript	c.10004C>T	p.Thr3335Met	missense_variant	65/80
DNAH1	XM_017006130.2 linkuse as main transcript	c.9935C>T	p.Thr3312Met	missense_variant	64/79
DNAH1	XM_017006131.2 linkuse as main transcript	c.9878C>T	p.Thr3293Met	missense_variant	64/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.9935C>T	p.Thr3312Met	missense_variant	63/78	1	NM_015512.5	P1	Q9P2D7-4

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

577

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000975

AC:

241

AN:

247282

Hom.:

AF XY:

0.000723

AC XY:

AN XY:

134170

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000359

AC:

524

AN:

1460980

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

221

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.0129

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00381

AC:

579

AN:

152142

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

270

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000754

Hom.:

Bravo

AF:

0.00438

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0144

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

DNAH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.040

Sift

Benign

0.049

Sift4G

Benign

0.077

Vest4

0.36

MVP

0.37

MPC

0.15

ClinPred

0.017

GERP RS

2.6

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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