rs111539520

Positions:

• chr16-20963418-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001347886.2(DNAH3):​c.10328G>A​(p.Arg3443Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,614,088 control chromosomes in the GnomAD database, including 1,202 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (57 hom., cov: 31)
  • Exomes 𝑓: 0.036 (1145 hom.)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035296977).
• BP6: Variant 16-20963418-C-T is Benign according to our data. Variant chr16-20963418-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-20963418-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0216 (3282/152204) while in subpopulation NFE AF= 0.037 (2518/68000). AF 95% confidence interval is 0.0358. There are 57 homozygotes in gnomad4. There are 1407 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH3	NM_001347886.2	c.10328G>A	p.Arg3443Gln	missense_variant	53/62	ENST00000698260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH3	ENST00000698260.1	c.10328G>A	p.Arg3443Gln	missense_variant	53/62		NM_001347886.2	P1
DNAH3	ENST00000261383.3	c.10466G>A	p.Arg3489Gln	missense_variant	53/62	1
DNAH3	ENST00000685858.1	c.10508G>A	p.Arg3503Gln	missense_variant	53/62

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3282 AN: 152086 Hom.: 57 Cov.: 31

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0255

GnomAD3 exomes AF: 0.0198 AC: 4984 AN: 251446 Hom.: 83 AF XY: 0.0195 AC XY: 2651 AN XY: 135902

Gnomad AFR exome AF: 0.00707

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00350

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0356 AC: 52085 AN: 1461884 Hom.: 1145 Cov.: 32 AF XY: 0.0345 AC XY: 25056 AN XY: 727240

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0438

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0216 AC: 3282 AN: 152204 Hom.: 57 Cov.: 31 AF XY: 0.0189 AC XY: 1407 AN XY: 74414

Gnomad4 AFR AF: 0.00792

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00970

Gnomad4 NFE AF: 0.0370

Gnomad4 OTH AF: 0.0252

Alfa AF: 0.0318 Hom.: 153

Bravo AF: 0.0218

TwinsUK AF: 0.0523 AC: 194

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.0100 AC: 44

ESP6500EA AF: 0.0400 AC: 344

ExAC AF: 0.0200 AC: 2434

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0355

EpiControl AF: 0.0339

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.7
DANN	Benign	0.24
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.053	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.056
Sift	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.040
MPC		0.11
ClinPred		0.0018	T
GERP RS		0.90
Varity_R		0.031
gMVP		0.20

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: rs111539520; hg19: chr16-20974740;