rs61734637

Positions:

• chr3-52399135-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.12375A>T​(p.Thr4125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,974 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (66 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.73

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=-0.82).
• BP6: Variant 3-52399135-A-T is Benign according to our data. Variant chr3-52399135-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 478408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00387 (589/152326) while in subpopulation SAS AF= 0.0234 (113/4822). AF 95% confidence interval is 0.0199. There are 4 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.12375A>T	p.Thr4125=	synonymous_variant	76/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.12444A>T	p.Thr4148=	synonymous_variant	78/80
DNAH1	XM_017006130.2	c.12375A>T	p.Thr4125=	synonymous_variant	77/79
DNAH1	XM_017006131.2	c.12318A>T	p.Thr4106=	synonymous_variant	77/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.12375A>T	p.Thr4125=	synonymous_variant	76/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.12832A>T		non_coding_transcript_exon_variant	75/77	2
DNAH1	ENST00000488988.5	n.4161A>T		non_coding_transcript_exon_variant	23/25	2
DNAH1	ENST00000490713.5	c.*157A>T		3_prime_UTR_variant, NMD_transcript_variant	18/20	5

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152208 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00599 AC: 1480 AN: 247044 Hom.: 10 AF XY: 0.00703 AC XY: 944 AN XY: 134226

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00779

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00586 AC: 8570 AN: 1461648 Hom.: 66 Cov.: 31 AF XY: 0.00638 AC XY: 4637 AN XY: 727102

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00783

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00568

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152326 Hom.: 4 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74480

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00732

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00370 Hom.: 2

Bravo AF: 0.00306

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00498

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	Aug 25, 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	-0.82
CADD	Benign	2.7
DANN	Benign	0.79

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: rs61734637; hg19: chr3-52433151;