16-20952510-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001347886.2(DNAH3):c.10973G>A(p.Arg3658Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00795 in 1,613,198 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.65

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014439553).
• BP6: Variant 16-20952510-C-T is Benign according to our data. Variant chr16-20952510-C-T is described in ClinVar as [Benign]. Clinvar id is 774340.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 938 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH3	NM_001347886.2	c.10973G>A	p.Arg3658Lys	missense_variant	56/62	ENST00000698260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH3	ENST00000698260.1	c.10973G>A	p.Arg3658Lys	missense_variant	56/62		NM_001347886.2	P1
DNAH3	ENST00000261383.3	c.11111G>A	p.Arg3704Lys	missense_variant	56/62	1
DNAH3	ENST00000685858.1	c.11153G>A	p.Arg3718Lys	missense_variant	56/62

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 938 AN: 152130 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00552 AC: 1388 AN: 251342 Hom.: 11 AF XY: 0.00572 AC XY: 777 AN XY: 135828

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00934

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00814 AC: 11890 AN: 1460950 Hom.: 69 Cov.: 29 AF XY: 0.00786 AC XY: 5711 AN XY: 726774

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00597

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.000992

Gnomad4 NFE exome AF: 0.00980

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.00616 AC: 938 AN: 152248 Hom.: 4 Cov.: 31 AF XY: 0.00590 AC XY: 439 AN XY: 74448

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00947

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00864 Hom.: 6

Bravo AF: 0.00692

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00572 AC: 694

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.67
MVP		0.21
MPC		0.14
ClinPred		0.034	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.73

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: rs147732992; hg19: chr16-20963832; COSMIC: COSV99079187;