rs74762885

Variant names:

• chr3-52322110-G-A
• rs74762885
• NM_015512.5:c.-34-299G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.-34-299G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 152,256 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.012 (17 hom., cov: 32)
• Consequence: DNAH1 NM_015512.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-52322110-G-A is Benign according to our data. Variant chr3-52322110-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1218326.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1795/152256) while in subpopulation SAS AF = 0.0334 (161/4818). AF 95% confidence interval is 0.0292. There are 17 homozygotes in GnomAd4. There are 853 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.-34-299G>A		intron	N/A	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.-34-299G>A		intron	N/A	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.228-299G>A		intron	N/A
	DNAH1	ENST00000497875.1	TSL:2	n.132-299G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1797 AN: 152138 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0118 AC: 1795 AN: 152256 Hom.: 17 Cov.: 32 AF XY: 0.0115 AC XY: 853 AN XY: 74438

African (AFR) AF: 0.00279 AC: 116 AN: 41546

American (AMR) AF: 0.0120 AC: 183 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4818

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1168 AN: 68008

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0156 Hom.: 25

Bravo AF: 0.0112

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.47
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs74762885; hg19: chr3-52356126;