3-52366724-G-C

Variant names:

• chr3-52366724-G-C
• rs3752819
• NM_015512.5:c.5611-9G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):​c.5611-9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,603,666 control chromosomes in the GnomAD database, including 23,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2723 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20655 hom.)
• Consequence: DNAH1 NM_015512.5 intron
• Scores: Splicing: ADA: 0.00001498
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.375
• Publications: 11 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, LIMITED Submitted by: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-52366724-G-C is Benign according to our data. Variant chr3-52366724-G-C is described in ClinVar as Benign. ClinVar VariationId is 402599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

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.5611-9G>C		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.5611-9G>C		intron	N/A	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.5872-9G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.178 AC: 26933 AN: 151496 Hom.: 2719 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.0888

Gnomad FIN AF: 0.0834

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.136 AC: 33304 AN: 244968 AF XY: 0.134

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0887

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.163 AC: 236378 AN: 1452052 Hom.: 20655 Cov.: 36 AF XY: 0.160 AC XY: 115526 AN XY: 720770

African (AFR) AF: 0.270 AC: 9008 AN: 33342

American (AMR) AF: 0.116 AC: 5169 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3885 AN: 25680

East Asian (EAS) AF: 0.0170 AC: 673 AN: 39494

South Asian (SAS) AF: 0.0957 AC: 8184 AN: 85480

European-Finnish (FIN) AF: 0.0926 AC: 4914 AN: 53058

Middle Eastern (MID) AF: 0.149 AC: 856 AN: 5738

European-Non Finnish (NFE) AF: 0.175 AC: 193670 AN: 1105004

Other (OTH) AF: 0.167 AC: 10019 AN: 59872

GnomAD4 genome AF: 0.178 AC: 26954 AN: 151614 Hom.: 2723 Cov.: 32 AF XY: 0.171 AC XY: 12659 AN XY: 74102

African (AFR) AF: 0.259 AC: 10659 AN: 41220

American (AMR) AF: 0.147 AC: 2243 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3468

East Asian (EAS) AF: 0.0226 AC: 116 AN: 5138

South Asian (SAS) AF: 0.0893 AC: 429 AN: 4806

European-Finnish (FIN) AF: 0.0834 AC: 877 AN: 10518

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11487 AN: 67902

Other (OTH) AF: 0.190 AC: 399 AN: 2098

Alfa AF: 0.101 Hom.: 189

Bravo AF: 0.186

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.45
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs3752819; hg19: chr3-52400740; COSMIC: COSV70239289; COSMIC: COSV70239289;