rs61734638

Positions:

• chr3-52360039-G-A
• chr3-52360039-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.4531G>A​(p.Val1511Met) variant causes a missense change. The variant allele was found at a frequency of 0.0253 in 1,613,938 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (41 hom., cov: 33)
  • Exomes 𝑓: 0.026 (578 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.92

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=0.004373938).
• BP6: Variant 3-52360039-G-A is Benign according to our data. Variant chr3-52360039-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52360039-G-A is described in Lovd as [Pathogenic]. Variant chr3-52360039-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2738/152372) while in subpopulation NFE AF= 0.0286 (1943/68032). AF 95% confidence interval is 0.0275. There are 41 homozygotes in gnomad4. There are 1245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.4531G>A	p.Val1511Met	missense_variant	27/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.4531G>A	p.Val1511Met	missense_variant	28/80
DNAH1	XM_017006130.2	c.4531G>A	p.Val1511Met	missense_variant	28/79
DNAH1	XM_017006131.2	c.4531G>A	p.Val1511Met	missense_variant	28/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.4531G>A	p.Val1511Met	missense_variant	27/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.4792G>A		non_coding_transcript_exon_variant	27/77	2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2736 AN: 152254 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0186 AC: 4632 AN: 248978 Hom.: 63 AF XY: 0.0190 AC XY: 2572 AN XY: 135058

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00942

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0261 AC: 38164 AN: 1461566 Hom.: 578 Cov.: 32 AF XY: 0.0258 AC XY: 18784 AN XY: 727062

Gnomad4 AFR exome AF: 0.00406

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.00984

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0180 AC: 2738 AN: 152372 Hom.: 41 Cov.: 33 AF XY: 0.0167 AC XY: 1245 AN XY: 74506

Gnomad4 AFR AF: 0.00596

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00734

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0244 Hom.: 73

Bravo AF: 0.0183

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00627 AC: 27

ESP6500EA AF: 0.0291 AC: 248

ExAC AF: 0.0188 AC: 2284

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628, 29449551) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DNAH1: BP4, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.37	T
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.20
MPC		0.53
ClinPred		0.051	T
GERP RS		4.2
gMVP		0.64

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: rs61734638; hg19: chr3-52394055;