rs775730815

Positions:

• chr3-52396681-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015512.5(DNAH1):​c.11495del​(p.Arg3832LeufsTer64) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,510 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAH1 NM_015512.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.11495del	p.Arg3832LeufsTer64	frameshift_variant	72/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.11564del	p.Arg3855LeufsTer64	frameshift_variant	74/80		XP_016861618.1
DNAH1	XM_017006130.2	c.11495del	p.Arg3832LeufsTer64	frameshift_variant	73/79		XP_016861619.1
DNAH1	XM_017006131.2	c.11438del	p.Arg3813LeufsTer64	frameshift_variant	73/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.11495del	p.Arg3832LeufsTer64	frameshift_variant	72/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.11952del		non_coding_transcript_exon_variant	71/77	2
DNAH1	ENST00000488988.5	n.3281del		non_coding_transcript_exon_variant	19/25	2
DNAH1	ENST00000490713.5	c.2195del	p.Arg732LeufsTer64	frameshift_variant, NMD_transcript_variant	15/20	5		ENSP00000419071

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461510 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775730815; hg19: chr3-52430697;