rs11714402

Positions:

• chr3-52357719-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015512.5(DNAH1):​c.3964A>C​(p.Arg1322=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,579,880 control chromosomes in the GnomAD database, including 24,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2849 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22131 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.257

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-52357719-A-C is Benign according to our data. Variant chr3-52357719-A-C is described in ClinVar as [Benign]. Clinvar id is 402598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.257 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.3964A>C	p.Arg1322=	synonymous_variant	23/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.3964A>C	p.Arg1322=	synonymous_variant	24/80
DNAH1	XM_017006130.2	c.3964A>C	p.Arg1322=	synonymous_variant	24/79
DNAH1	XM_017006131.2	c.3964A>C	p.Arg1322=	synonymous_variant	24/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.3964A>C	p.Arg1322=	synonymous_variant	23/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.4225A>C		non_coding_transcript_exon_variant	23/77	2

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27791 AN: 152056 Hom.: 2845 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.139 AC: 27039 AN: 194792 Hom.: 2125 AF XY: 0.137 AC XY: 14419 AN XY: 105158

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0207

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.0889

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.171 AC: 243798 AN: 1427706 Hom.: 22131 Cov.: 33 AF XY: 0.169 AC XY: 119265 AN XY: 707098

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0936

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.183 AC: 27811 AN: 152174 Hom.: 2849 Cov.: 32 AF XY: 0.176 AC XY: 13086 AN XY: 74414

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0846

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.197

Alfa AF: 0.178 Hom.: 3314

Bravo AF: 0.190

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.2
DANN	Benign	0.40

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: rs11714402; hg19: chr3-52391735; COSMIC: COSV70229072; COSMIC: COSV70229072;