rs365048

chr3-52396682-G-Achr3-52396682-G-Cchr3-52396682-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):c.11495G>A(p.Arg3832His) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,718 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3832C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (6 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16767171).
• BP6: Variant 3-52396682-G-A is Benign according to our data. Variant chr3-52396682-G-A is described in ClinVar as [Benign]. Clinvar id is 478401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00463 (704/152214) while in subpopulation AFR AF= 0.0157 (653/41502). AF 95% confidence interval is 0.0147. There are 7 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.11495G>A	p.Arg3832His	missense_variant	72/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.11564G>A	p.Arg3855His	missense_variant	74/80
DNAH1	XM_017006130.2	c.11495G>A	p.Arg3832His	missense_variant	73/79
DNAH1	XM_017006131.2	c.11438G>A	p.Arg3813His	missense_variant	73/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.11495G>A	p.Arg3832His	missense_variant	72/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.11952G>A		non_coding_transcript_exon_variant	71/77	2
DNAH1	ENST00000488988.5	n.3281G>A		non_coding_transcript_exon_variant	19/25	2
DNAH1	ENST00000490713.5	c.2195G>A	p.Arg732His	missense_variant, NMD_transcript_variant	15/20	5

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152096 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.000854 AC: 1248 AN: 1461504 Hom.: 6 Cov.: 34 AF XY: 0.000816 AC XY: 593 AN XY: 727018

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000480

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.00463 AC: 704 AN: 152214 Hom.: 7 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74430

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.000796 Hom.: 1

Bravo AF: 0.00538

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	30
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.17	T
Sift4G	Uncertain	0.0020	D
Vest4		0.63
gMVP		0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs365048; hg19: chr3-52430698;