rs61739897

Variant names:

• chr3-52358734-C-T
• rs61739897
• NM_015512.5:c.4263C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52358734-C-T
• chr3-52358734-C-A
• chr3-52358734-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.4263C>T​(p.Pro1421Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,612,128 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.221
• Publications: 2 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=-0.73).
• BP6: Variant 3-52358734-C-T is Benign according to our data. Variant chr3-52358734-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.221 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00373 (568/152276) while in subpopulation SAS AF = 0.023 (111/4824). AF 95% confidence interval is 0.0195. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.4263C>T	p.Pro1421Pro	synonymous	Exon 25 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.4263C>T	p.Pro1421Pro	synonymous	Exon 25 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.4524C>T		non_coding_transcript_exon	Exon 25 of 77

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 569 AN: 152158 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00561 AC: 1386 AN: 246870 AF XY: 0.00667

Gnomad AFR exome AF: 0.000849

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00358

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00577 AC: 8425 AN: 1459852 Hom.: 65 Cov.: 31 AF XY: 0.00631 AC XY: 4586 AN XY: 726224

African (AFR) AF: 0.000629 AC: 21 AN: 33408

American (AMR) AF: 0.00219 AC: 98 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26092

East Asian (EAS) AF: 0.00376 AC: 149 AN: 39652

South Asian (SAS) AF: 0.0232 AC: 2002 AN: 86144

European-Finnish (FIN) AF: 0.00152 AC: 80 AN: 52478

Middle Eastern (MID) AF: 0.00521 AC: 29 AN: 5568

European-Non Finnish (NFE) AF: 0.00510 AC: 5665 AN: 1111548

Other (OTH) AF: 0.00562 AC: 339 AN: 60308

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152276 Hom.: 4 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74460

African (AFR) AF: 0.000890 AC: 37 AN: 41558

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5174

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00323 Hom.: 2

Bravo AF: 0.00290

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00505

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.73
CADD	Benign	5.6
DANN	Benign	0.62
PhyloP100		-0.22
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: rs61739897; hg19: chr3-52392750;