rs3115446

Variant names:

• chr16-20997368-T-C
• rs3115446
• NM_001347886.2:c.6378A>G

Variant summary

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

The NM_001347886.2(DNAH3):​c.6378A>G​(p.Lys2126Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,613,834 control chromosomes in the GnomAD database, including 181,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19500 hom., cov: 32)
  • Exomes 𝑓: 0.47 (161644 hom.)
• Consequence: DNAH3 NM_001347886.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.381
• Publications: 20 publications found

Genes affected

DNAH3 (HGNC:2949): (dynein axonemal heavy chain 3) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

DNAH3 Gene-Disease associations (from GenCC):

• male infertility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-20997368-T-C is Benign according to our data. Variant chr16-20997368-T-C is described in ClinVar as Benign. ClinVar VariationId is 402721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.381 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347886.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.6378A>G	p.Lys2126Lys	synonymous	Exon 44 of 62	NP_001334815.1
	DNAH3	NM_017539.2		c.6516A>G	p.Lys2172Lys	synonymous	Exon 44 of 62	NP_060009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	ENST00000698260.1	MANE Select	c.6378A>G	p.Lys2126Lys	synonymous	Exon 44 of 62	ENSP00000513632.1
	DNAH3	ENST00000261383.3	TSL:1	c.6516A>G	p.Lys2172Lys	synonymous	Exon 44 of 62	ENSP00000261383.3
	DNAH3	ENST00000685858.1		c.6558A>G	p.Lys2186Lys	synonymous	Exon 44 of 62	ENSP00000508756.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76427 AN: 151922 Hom.: 19487 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.491 AC: 123414 AN: 251320 AF XY: 0.495

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.468 AC: 684345 AN: 1461794 Hom.: 161644 Cov.: 60 AF XY: 0.472 AC XY: 343167 AN XY: 727198

African (AFR) AF: 0.590 AC: 19756 AN: 33480

American (AMR) AF: 0.479 AC: 21435 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 11376 AN: 26134

East Asian (EAS) AF: 0.495 AC: 19642 AN: 39694

South Asian (SAS) AF: 0.597 AC: 51520 AN: 86246

European-Finnish (FIN) AF: 0.493 AC: 26336 AN: 53386

Middle Eastern (MID) AF: 0.428 AC: 2470 AN: 5766

European-Non Finnish (NFE) AF: 0.452 AC: 502756 AN: 1111974

Other (OTH) AF: 0.481 AC: 29054 AN: 60394

GnomAD4 genome AF: 0.503 AC: 76481 AN: 152040 Hom.: 19500 Cov.: 32 AF XY: 0.507 AC XY: 37683 AN XY: 74306

African (AFR) AF: 0.588 AC: 24406 AN: 41488

American (AMR) AF: 0.486 AC: 7435 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1510 AN: 3470

East Asian (EAS) AF: 0.490 AC: 2530 AN: 5158

South Asian (SAS) AF: 0.612 AC: 2950 AN: 4818

European-Finnish (FIN) AF: 0.501 AC: 5278 AN: 10544

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30852 AN: 67958

Other (OTH) AF: 0.465 AC: 982 AN: 2112

Alfa AF: 0.470 Hom.: 54210

Bravo AF: 0.501

Asia WGS AF: 0.580 AC: 2015 AN: 3478

EpiCase AF: 0.449

EpiControl AF: 0.442

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.1
DANN	Benign	0.65
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs3115446; hg19: chr16-21008690; COSMIC: COSV54506044;