16-20985659-G-C

Variant names:

• chr16-20985659-G-C
• rs61734980
• NM_001347886.2:c.6945C>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001347886.2(DNAH3):​c.6945C>G​(p.Leu2315Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,614,154 control chromosomes in the GnomAD database, including 2,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (131 hom., cov: 31)
  • Exomes 𝑓: 0.047 (1870 hom.)
• Consequence: DNAH3 NM_001347886.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0920

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-20985659-G-C is Benign according to our data. Variant chr16-20985659-G-C is described in ClinVar as [Benign]. Clinvar id is 402720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.6945C>G	p.Leu2315Leu	synonymous_variant	Exon 48 of 62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.6945C>G	p.Leu2315Leu	synonymous_variant	Exon 48 of 62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.7083C>G	p.Leu2361Leu	synonymous_variant	Exon 48 of 62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.7125C>G	p.Leu2375Leu	synonymous_variant	Exon 48 of 62			ENSP00000508756.1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5398 AN: 152154 Hom.: 131 Cov.: 31

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0364 AC: 9161 AN: 251422 Hom.: 220 AF XY: 0.0375 AC XY: 5092 AN XY: 135882

Gnomad AFR exome AF: 0.00548

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0580

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0156

Gnomad FIN exome AF: 0.0380

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0474 AC: 69321 AN: 1461882 Hom.: 1870 Cov.: 32 AF XY: 0.0468 AC XY: 34061 AN XY: 727240

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.0291

Gnomad4 ASJ exome AF: 0.0598

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0540

Gnomad4 OTH exome AF: 0.0438

GnomAD4 genome AF: 0.0354 AC: 5396 AN: 152272 Hom.: 131 Cov.: 31 AF XY: 0.0346 AC XY: 2579 AN XY: 74456

Gnomad4 AFR AF: 0.00919

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0600

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0352

Gnomad4 NFE AF: 0.0531

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0409 Hom.: 54

Bravo AF: 0.0348

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.9
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs61734980; hg19: chr16-20996981;