rs374941590

Positions:

• chr3-52326885-A-G

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.732A>G​(p.Pro244Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000943 in 1,612,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (3 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.66

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]

DNAH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-52326885-A-G is Benign according to our data. Variant chr3-52326885-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 544651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52326885-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000959 (140/1460198) while in subpopulation MID AF= 0.00764 (44/5756). AF 95% confidence interval is 0.00585. There are 3 homozygotes in gnomad4_exome. There are 78 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.732A>G	p.Pro244Pro	synonymous_variant	5/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.732A>G	p.Pro244Pro	synonymous_variant	6/80		XP_016861618.1
DNAH1	XM_017006130.2	c.732A>G	p.Pro244Pro	synonymous_variant	6/79		XP_016861619.1
DNAH1	XM_017006131.2	c.732A>G	p.Pro244Pro	synonymous_variant	6/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.732A>G	p.Pro244Pro	synonymous_variant	5/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.993A>G		non_coding_transcript_exon_variant	5/77	2
DNAH1	ENST00000497875.1	n.897A>G		non_coding_transcript_exon_variant	6/21	2

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 14 AN: 151734 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 246560 Hom.: 0 AF XY: 0.000142 AC XY: 19 AN XY: 133848

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000717

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000959 AC: 140 AN: 1460198 Hom.: 3 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 726322

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000337

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151852 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74188

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.2
DANN	Benign	0.67

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: rs374941590; hg19: chr3-52360901;