rs75513160

Variant names:

• chr3-52392856-G-A
• rs75513160
• NM_015512.5:c.10305G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015512.5(DNAH1):​c.10305G>A​(p.Thr3435Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,597,196 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 29)
  • Exomes 𝑓: 0.0019 (66 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.32
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-52392856-G-A is Benign according to our data. Variant chr3-52392856-G-A is described in ClinVar as Benign. ClinVar VariationId is 478377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 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.10305G>A	p.Thr3435Thr	synonymous	Exon 65 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.10305G>A	p.Thr3435Thr	synonymous	Exon 65 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.10762G>A		non_coding_transcript_exon	Exon 64 of 77
	DNAH1	ENST00000488988.5	TSL:2	n.2091G>A		non_coding_transcript_exon	Exon 12 of 25

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2205 AN: 143144 Hom.: 64 Cov.: 29

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.000226

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000703

Gnomad OTH AF: 0.0107

GnomAD2 exomes AF: 0.00391 AC: 969 AN: 247530 AF XY: 0.00282

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00189 AC: 2742 AN: 1453972 Hom.: 66 Cov.: 39 AF XY: 0.00165 AC XY: 1190 AN XY: 721488

African (AFR) AF: 0.0564 AC: 1881 AN: 33370

American (AMR) AF: 0.00202 AC: 90 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.000256 AC: 22 AN: 86092

European-Finnish (FIN) AF: 0.000320 AC: 17 AN: 53174

Middle Eastern (MID) AF: 0.00453 AC: 26 AN: 5742

European-Non Finnish (NFE) AF: 0.000427 AC: 472 AN: 1105592

Other (OTH) AF: 0.00390 AC: 234 AN: 59962

GnomAD4 genome AF: 0.0154 AC: 2211 AN: 143224 Hom.: 64 Cov.: 29 AF XY: 0.0148 AC XY: 1021 AN XY: 68876

African (AFR) AF: 0.0544 AC: 2084 AN: 38276

American (AMR) AF: 0.00399 AC: 53 AN: 13290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4828

South Asian (SAS) AF: 0.000441 AC: 2 AN: 4538

European-Finnish (FIN) AF: 0.000226 AC: 2 AN: 8862

Middle Eastern (MID) AF: 0.00725 AC: 2 AN: 276

European-Non Finnish (NFE) AF: 0.000703 AC: 47 AN: 66826

Other (OTH) AF: 0.0106 AC: 21 AN: 1974

Alfa AF: 0.00646 Hom.: 13

Bravo AF: 0.0175

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000830

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	-0.43
CADD	Benign	4.8
DANN	Benign	0.72
PhyloP100		-1.3
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: rs75513160; hg19: chr3-52426872;