rs143443167

chr3-52392989-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015512.5(DNAH1):c.10438A>G(p.Ile3480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,274 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.62

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049548).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.10438A>G	p.Ile3480Val	missense_variant	65/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.10507A>G	p.Ile3503Val	missense_variant	67/80
DNAH1	XM_017006130.2	c.10438A>G	p.Ile3480Val	missense_variant	66/79
DNAH1	XM_017006131.2	c.10381A>G	p.Ile3461Val	missense_variant	66/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.10438A>G	p.Ile3480Val	missense_variant	65/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.10895A>G		non_coding_transcript_exon_variant	64/77	2
DNAH1	ENST00000488988.5	n.2224A>G		non_coding_transcript_exon_variant	12/25	2
DNAH1	ENST00000490713.5	c.1138A>G	p.Ile380Val	missense_variant, NMD_transcript_variant	8/20	5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 151642 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000811 AC: 202 AN: 249180 Hom.: 1 AF XY: 0.000799 AC XY: 108 AN XY: 135178

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00184 AC: 2682 AN: 1461518 Hom.: 4 Cov.: 38 AF XY: 0.00177 AC XY: 1288 AN XY: 727020

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000694

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00101 AC: 153 AN: 151756 Hom.: 2 Cov.: 32 AF XY: 0.000769 AC XY: 57 AN XY: 74160

Gnomad4 AFR AF: 0.000460

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000627

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.000929

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00178 AC: 15

ExAC AF: 0.000793 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3480 of the DNAH1 protein (p.Ile3480Val). This variant is present in population databases (rs143443167, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 478384). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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

Jan 04, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 05, 2020

- -

DNAH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.13
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.021	D
Vest4		0.54
MVP		0.59
MPC		0.36
ClinPred		0.023	T
GERP RS		4.7
gMVP		0.38

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

Other links and lift over

dbSNP: rs143443167; hg19: chr3-52427005;