rs185397176

chr3-52388589-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_015512.5(DNAH1):c.9343C>T(p.Arg3115Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,612,022 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3115Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.873

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18337005).
• BP6: Variant 3-52388589-C-T is Benign according to our data. Variant chr3-52388589-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478511.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.9343C>T	p.Arg3115Trp	missense_variant	58/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.9412C>T	p.Arg3138Trp	missense_variant	60/80
DNAH1	XM_017006130.2	c.9343C>T	p.Arg3115Trp	missense_variant	59/79
DNAH1	XM_017006131.2	c.9412C>T	p.Arg3138Trp	missense_variant	60/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.9343C>T	p.Arg3115Trp	missense_variant	58/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.9604C>T		non_coding_transcript_exon_variant	58/77	2
DNAH1	ENST00000488988.5	n.933C>T		non_coding_transcript_exon_variant	6/25	2
DNAH1	ENST00000490713.5	c.43C>T	p.Arg15Trp	missense_variant, NMD_transcript_variant	1/20	5

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000884 AC: 216 AN: 244434 Hom.: 0 AF XY: 0.000857 AC XY: 114 AN XY: 133080

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.000792

Gnomad ASJ exome AF: 0.00383

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.00170 AC: 2488 AN: 1459694 Hom.: 2 Cov.: 32 AF XY: 0.00164 AC XY: 1188 AN XY: 726056

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000921

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74484

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.00143

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00152 AC: 13

ExAC AF: 0.000726 AC: 88

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2022	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

DNAH1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	0.72	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.86
MVP		0.55
MPC		0.59
ClinPred		0.11	T
GERP RS		0.70
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs185397176; hg19: chr3-52422605; COSMIC: COSV70231278; COSMIC: COSV70231278;