rs111770788

chr16-20987398-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001347886.2(DNAH3):c.6795C>T(p.Phe2265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,614,110 control chromosomes in the GnomAD database, including 1,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1250 hom.)
• Consequence: DNAH3 NM_001347886.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 16-20987398-G-A is Benign according to our data. Variant chr16-20987398-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.023 (3503/152258) while in subpopulation NFE AF= 0.0385 (2618/68030). AF 95% confidence interval is 0.0373. There are 65 homozygotes in gnomad4. There are 1518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3503 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH3	NM_001347886.2	c.6795C>T	p.Phe2265=	synonymous_variant	47/62	ENST00000698260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH3	ENST00000698260.1	c.6795C>T	p.Phe2265=	synonymous_variant	47/62		NM_001347886.2	P1
DNAH3	ENST00000261383.3	c.6933C>T	p.Phe2311=	synonymous_variant	47/62	1
DNAH3	ENST00000685858.1	c.6975C>T	p.Phe2325=	synonymous_variant	47/62

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3503 AN: 152140 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00825

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0210 AC: 5276 AN: 251458 Hom.: 93 AF XY: 0.0208 AC XY: 2820 AN XY: 135900

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0369 AC: 53942 AN: 1461852 Hom.: 1250 Cov.: 31 AF XY: 0.0357 AC XY: 25956 AN XY: 727232

Gnomad4 AFR exome AF: 0.00559

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0230 AC: 3503 AN: 152258 Hom.: 65 Cov.: 32 AF XY: 0.0204 AC XY: 1518 AN XY: 74452

Gnomad4 AFR AF: 0.00823

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0385

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0299 Hom.: 40

Bravo AF: 0.0237

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0366

EpiControl AF: 0.0350

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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, silent variant not near splice site -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	8.4
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111770788; hg19: chr16-20998720;