chr16-20997368-T-C

Position:

• chr16-20997368-T-C

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.6378A>G​(p.Lys2126Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,613,834 control chromosomes in the GnomAD database, including 181,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19500 hom., cov: 32)
  • Exomes 𝑓: 0.47 (161644 hom.)
• Consequence: DNAH3 NM_001347886.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.381

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]

DNAH3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-20997368-T-C is Benign according to our data. Variant chr16-20997368-T-C is described in ClinVar as [Benign]. Clinvar id is 402721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.381 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.6378A>G	p.Lys2126Lys	synonymous_variant	44/62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.6378A>G	p.Lys2126Lys	synonymous_variant	44/62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.6516A>G	p.Lys2172Lys	synonymous_variant	44/62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.6558A>G	p.Lys2186Lys	synonymous_variant	44/62			ENSP00000508756.1
DNAH3	ENST00000572640.5	n.3227A>G		non_coding_transcript_exon_variant	21/21	2

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76427 AN: 151922 Hom.: 19487 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.491 AC: 123414 AN: 251320 Hom.: 30744 AF XY: 0.495 AC XY: 67205 AN XY: 135830

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.521

Gnomad SAS exome AF: 0.603

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.468 AC: 684345 AN: 1461794 Hom.: 161644 Cov.: 60 AF XY: 0.472 AC XY: 343167 AN XY: 727198

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.479

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.452

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.503 AC: 76481 AN: 152040 Hom.: 19500 Cov.: 32 AF XY: 0.507 AC XY: 37683 AN XY: 74306

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.454

Gnomad4 OTH AF: 0.465

Alfa AF: 0.462 Hom.: 32660

Bravo AF: 0.501

Asia WGS AF: 0.580 AC: 2015 AN: 3478

EpiCase AF: 0.449

EpiControl AF: 0.442

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.1
DANN	Benign	0.65

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: rs3115446; hg19: chr16-21008690; COSMIC: COSV54506044;