rs144605025

Positions:

• chr3-52396668-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015512.5(DNAH1):​c.11481C>T​(p.Asn3827=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.17

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-52396668-C-T is Benign according to our data. Variant chr3-52396668-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.11481C>T	p.Asn3827=	synonymous_variant	72/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.11550C>T	p.Asn3850=	synonymous_variant	74/80
DNAH1	XM_017006130.2	c.11481C>T	p.Asn3827=	synonymous_variant	73/79
DNAH1	XM_017006131.2	c.11424C>T	p.Asn3808=	synonymous_variant	73/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.11481C>T	p.Asn3827=	synonymous_variant	72/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.11938C>T		non_coding_transcript_exon_variant	71/77	2
DNAH1	ENST00000488988.5	n.3267C>T		non_coding_transcript_exon_variant	19/25	2
DNAH1	ENST00000490713.5	c.2181C>T	p.Asn727=	synonymous_variant, NMD_transcript_variant	15/20	5

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000868 AC: 216 AN: 248882 Hom.: 0 AF XY: 0.000918 AC XY: 124 AN XY: 135032

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.00118 AC: 1731 AN: 1461398 Hom.: 2 Cov.: 34 AF XY: 0.00117 AC XY: 848 AN XY: 726962

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74436

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000873

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00160

ClinVar

Significance: Likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

DNAH1: BP4, BP7 -

DNAH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2020

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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.18
DANN	Benign	0.77

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: rs144605025; hg19: chr3-52430684;