rs140275399

chr3-52353165-G-Achr3-52353165-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):c.3090G>A(p.Ala1030=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,614,012 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1030A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (72 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00900

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 3-52353165-G-A is Benign according to our data. Variant chr3-52353165-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.009 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00435 (662/152344) while in subpopulation SAS AF= 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 5 homozygotes in gnomad4. There are 337 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.3090G>A	p.Ala1030=	synonymous_variant	19/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.3090G>A	p.Ala1030=	synonymous_variant	20/80
DNAH1	XM_017006130.2	c.3090G>A	p.Ala1030=	synonymous_variant	20/79
DNAH1	XM_017006131.2	c.3090G>A	p.Ala1030=	synonymous_variant	20/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.3090G>A	p.Ala1030=	synonymous_variant	19/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.3351G>A		non_coding_transcript_exon_variant	19/77	2
DNAH1	ENST00000497875.1	n.3255G>A		non_coding_transcript_exon_variant	20/21	2

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 663 AN: 152226 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00648 AC: 1615 AN: 249082 Hom.: 10 AF XY: 0.00750 AC XY: 1014 AN XY: 135140

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0124

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00626 AC: 9143 AN: 1461668 Hom.: 72 Cov.: 31 AF XY: 0.00677 AC XY: 4923 AN XY: 727118

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152344 Hom.: 5 Cov.: 33 AF XY: 0.00452 AC XY: 337 AN XY: 74510

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00374

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

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
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140275399; hg19: chr3-52387181;