chr3-52370511-G-A

Position:

chr3-52370511-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_015512.5(DNAH1):c.6293G>A(p.Arg2098His) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 3.90

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020444632).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000192 (281/1461654) while in subpopulation MID AF= 0.00451 (26/5768). AF 95% confidence interval is 0.00316. There are 0 homozygotes in gnomad4_exome. There are 147 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAH1	NM_015512.5 linkuse as main transcript	c.6293G>A	p.Arg2098His	missense_variant	40/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 linkuse as main transcript	c.6362G>A	p.Arg2121His	missense_variant	42/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.6293G>A	p.Arg2098His	missense_variant	41/79		XP_016861619.1
DNAH1	XM_017006131.2 linkuse as main transcript	c.6362G>A	p.Arg2121His	missense_variant	42/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.6293G>A	p.Arg2098His	missense_variant	40/78	1	NM_015512.5	ENSP00000401514	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.6554G>A		non_coding_transcript_exon_variant	40/77	2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000237

AC:

AN:

249116

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000192

AC:

281

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000158

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.000248

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2098 of the DNAH1 protein (p.Arg2098His). This variant is present in population databases (rs373906923, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 478476). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Nov 11, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DNAH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

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

0.099

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.82

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.77

M_CAP

Benign

0.0040

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

REVEL

Benign

0.027

Sift

Benign

0.28

Sift4G

Benign

0.19

Vest4

0.21

MVP

0.23

MPC

0.16

ClinPred

0.021

GERP RS

3.7

gMVP

0.31

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