rs200175873

Variant names:

• chr3-52363114-C-T
• rs200175873
• NM_015512.5:c.5214C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.5214C>T​(p.Phe1738Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000157 in 1,613,888 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.04
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-52363114-C-T is Benign according to our data. Variant chr3-52363114-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 478457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000161 (235/1461654) while in subpopulation MID AF = 0.00538 (31/5766). AF 95% confidence interval is 0.00389. There are 3 homozygotes in GnomAdExome4. There are 137 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.5214C>T	p.Phe1738Phe	synonymous	Exon 32 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.5214C>T	p.Phe1738Phe	synonymous	Exon 32 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.5475C>T		non_coding_transcript_exon	Exon 32 of 77

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000325 AC: 81 AN: 249206 AF XY: 0.000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461654 Hom.: 3 Cov.: 32 AF XY: 0.000188 AC XY: 137 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86254

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

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5766

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111840

Other (OTH) AF: 0.000298 AC: 18 AN: 60372

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	-0.29
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs200175873; hg19: chr3-52397130;