NM_015512.5:c.9783C>T

Variant names:

• chr3-52391220-C-T
• rs61733865
• NM_015512.5:c.9783C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015512.5(DNAH1):​c.9783C>T​(p.Arg3261Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,613,892 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (100 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.79
• 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, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-52391220-C-T is Benign according to our data. Variant chr3-52391220-C-T is described in ClinVar as Benign. ClinVar VariationId is 478517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0614 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.9783C>T	p.Arg3261Arg	synonymous	Exon 62 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.9783C>T	p.Arg3261Arg	synonymous	Exon 62 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000480649.1	TSL:4	c.216C>T	p.Arg72Arg	synonymous	Exon 3 of 5	ENSP00000418688.1	H7C506
	DNAH1	ENST00000486752.5	TSL:2	n.10240C>T		non_coding_transcript_exon	Exon 61 of 77

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2803 AN: 152174 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00475 AC: 1182 AN: 248690 AF XY: 0.00386

Gnomad AFR exome AF: 0.0674

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00202 AC: 2955 AN: 1461600 Hom.: 100 Cov.: 32 AF XY: 0.00175 AC XY: 1275 AN XY: 727062

African (AFR) AF: 0.0703 AC: 2354 AN: 33480

American (AMR) AF: 0.00367 AC: 164 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1111826

Other (OTH) AF: 0.00437 AC: 264 AN: 60372

GnomAD4 genome AF: 0.0184 AC: 2807 AN: 152292 Hom.: 75 Cov.: 33 AF XY: 0.0179 AC XY: 1336 AN XY: 74450

African (AFR) AF: 0.0634 AC: 2637 AN: 41562

American (AMR) AF: 0.00856 AC: 131 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00862 Hom.: 25

Bravo AF: 0.0219

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.13
DANN	Benign	0.58
PhyloP100		-5.8
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61733865; hg19: chr3-52425236;