rs330150

chr16-21039887-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001347886.2(DNAH3):c.4557C>G(p.Ile1519Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,612,088 control chromosomes in the GnomAD database, including 10,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1526 hom., cov: 31)
  • Exomes 𝑓: 0.11 (8722 hom.)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.540

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018554926).
• BP6: Variant 16-21039887-G-C is Benign according to our data. Variant chr16-21039887-G-C is described in ClinVar as [Benign]. Clinvar id is 402723.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH3	NM_001347886.2	c.4557C>G	p.Ile1519Met	missense_variant	33/62	ENST00000698260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH3	ENST00000698260.1	c.4557C>G	p.Ile1519Met	missense_variant	33/62		NM_001347886.2	P1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20013 AN: 152074 Hom.: 1525 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.0859

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.109 AC: 27317 AN: 251120 Hom.: 1627 AF XY: 0.108 AC XY: 14657 AN XY: 135710

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0827

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.0812

Gnomad FIN exome AF: 0.0936

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.106 AC: 154045 AN: 1459896 Hom.: 8722 Cov.: 31 AF XY: 0.105 AC XY: 76073 AN XY: 726352

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0850

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.0779

Gnomad4 FIN exome AF: 0.0909

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.132 AC: 20022 AN: 152192 Hom.: 1526 Cov.: 31 AF XY: 0.130 AC XY: 9700 AN XY: 74410

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.0715

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.119

Alfa AF: 0.113 Hom.: 797

Bravo AF: 0.137

TwinsUK AF: 0.0974 AC: 361

ALSPAC AF: 0.0924 AC: 356

ESP6500AA AF: 0.199 AC: 875

ESP6500EA AF: 0.101 AC: 868

ExAC AF: 0.110 AC: 13323

Asia WGS AF: 0.122 AC: 423 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.104

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	0.0000021	P;P
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.76
MPC		0.49
ClinPred		0.063	T
GERP RS		2.3
Varity_R		0.85
gMVP		0.64

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: rs330150; hg19: chr16-21051209; COSMIC: COSV54503953; COSMIC: COSV54503953;