3-52390937-C-T

Variant names:

• chr3-52390937-C-T
• rs61734628
• NM_015512.5:c.9624C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_015512.5(DNAH1):​c.9624C>T​(p.Ile3208Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,551,744 control chromosomes in the GnomAD database, including 1,481 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (776 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (705 hom.)
• Consequence: DNAH1 NM_015512.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.27
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.232).
• BP6: Variant 3-52390937-C-T is Benign according to our data. Variant chr3-52390937-C-T is described in ClinVar as Benign. ClinVar VariationId is 478514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.9624C>T	p.Ile3208Ile	splice_region synonymous	Exon 61 of 78	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.9624C>T	p.Ile3208Ile	splice_region synonymous	Exon 61 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000480649.1	TSL:4	c.57C>T	p.Ile19Ile	splice_region synonymous	Exon 2 of 5	ENSP00000418688.1	H7C506
	DNAH1	ENST00000486752.5	TSL:2	n.10081C>T		splice_region non_coding_transcript_exon	Exon 60 of 77

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8595 AN: 152136 Hom.: 772 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0154 AC: 2431 AN: 158064 AF XY: 0.0137

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00915

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000183

Gnomad FIN exome AF: 0.000472

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00992

GnomAD4 exome AF: 0.00928 AC: 12983 AN: 1399490 Hom.: 705 Cov.: 32 AF XY: 0.00895 AC XY: 6181 AN XY: 690238

African (AFR) AF: 0.203 AC: 6406 AN: 31590

American (AMR) AF: 0.0112 AC: 400 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35738

South Asian (SAS) AF: 0.0153 AC: 1210 AN: 79216

European-Finnish (FIN) AF: 0.000344 AC: 17 AN: 49428

Middle Eastern (MID) AF: 0.0104 AC: 59 AN: 5652

European-Non Finnish (NFE) AF: 0.00369 AC: 3976 AN: 1078934

Other (OTH) AF: 0.0157 AC: 911 AN: 58050

GnomAD4 genome AF: 0.0566 AC: 8622 AN: 152254 Hom.: 776 Cov.: 33 AF XY: 0.0548 AC XY: 4078 AN XY: 74452

African (AFR) AF: 0.189 AC: 7846 AN: 41520

American (AMR) AF: 0.0208 AC: 318 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 68024

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0268 Hom.: 216

Bravo AF: 0.0654

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.25
DANN	Benign	0.68
PhyloP100		-1.3
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61734628; hg19: chr3-52424953; COSMIC: COSV70228464; COSMIC: COSV70228464;