rs74363541

chr3-52349202-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):c.2308C>G(p.Gln770Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,458 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (49 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020835996).
• BP6: Variant 3-52349202-C-G is Benign according to our data. Variant chr3-52349202-C-G is described in ClinVar as [Benign]. Clinvar id is 478426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2308C>G	p.Gln770Glu	missense_variant	14/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2308C>G	p.Gln770Glu	missense_variant	15/80
DNAH1	XM_017006130.2	c.2308C>G	p.Gln770Glu	missense_variant	15/79
DNAH1	XM_017006131.2	c.2308C>G	p.Gln770Glu	missense_variant	15/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2308C>G	p.Gln770Glu	missense_variant	14/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2569C>G		non_coding_transcript_exon_variant	14/77	2
DNAH1	ENST00000497875.1	n.2473C>G		non_coding_transcript_exon_variant	15/21	2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2325 AN: 152196 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00359 AC: 889 AN: 247684 Hom.: 18 AF XY: 0.00268 AC XY: 361 AN XY: 134460

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00146 AC: 2139 AN: 1461144 Hom.: 49 Cov.: 33 AF XY: 0.00119 AC XY: 866 AN XY: 726836

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.0153 AC: 2334 AN: 152314 Hom.: 69 Cov.: 33 AF XY: 0.0148 AC XY: 1100 AN XY: 74468

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00477 Hom.: 6

Bravo AF: 0.0172

ESP6500AA AF: 0.0489 AC: 209

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00468 AC: 567

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Benign	0.28
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.12
Sift	Benign	0.82	T
Sift4G	Benign	1.0	T
Vest4		0.18
MVP		0.24
MPC		0.13
ClinPred		0.0091	T
GERP RS		4.2
gMVP		0.29

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: rs74363541; hg19: chr3-52383218;