NM_001347886.2:c.3291A>C

Variant names:

• chr16-21067372-T-G
• rs861424
• NM_001347886.2:c.3291A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001347886.2(DNAH3):​c.3291A>C​(p.Ala1097Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,613,456 control chromosomes in the GnomAD database, including 147,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1097A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.42 (13664 hom., cov: 31)
  • Exomes 𝑓: 0.42 (134032 hom.)
• Consequence: DNAH3 NM_001347886.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.251
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• male infertility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-21067372-T-G is Benign according to our data. Variant chr16-21067372-T-G is described in ClinVar as Benign. ClinVar VariationId is 402724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.251 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.3291A>C	p.Ala1097Ala	synonymous_variant	Exon 24 of 62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.3291A>C	p.Ala1097Ala	synonymous_variant	Exon 24 of 62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.3429A>C	p.Ala1143Ala	synonymous_variant	Exon 24 of 62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.3471A>C	p.Ala1157Ala	synonymous_variant	Exon 24 of 62			ENSP00000508756.1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63321 AN: 151866 Hom.: 13647 Cov.: 31

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.445 AC: 111818 AN: 251150 AF XY: 0.444

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.424 AC: 619363 AN: 1461470 Hom.: 134032 Cov.: 43 AF XY: 0.424 AC XY: 308309 AN XY: 727048

African (AFR) AF: 0.365 AC: 12217 AN: 33464

American (AMR) AF: 0.477 AC: 21341 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11557 AN: 26130

East Asian (EAS) AF: 0.708 AC: 28084 AN: 39694

South Asian (SAS) AF: 0.451 AC: 38879 AN: 86230

European-Finnish (FIN) AF: 0.457 AC: 24400 AN: 53412

Middle Eastern (MID) AF: 0.391 AC: 2252 AN: 5756

European-Non Finnish (NFE) AF: 0.409 AC: 454828 AN: 1111704

Other (OTH) AF: 0.427 AC: 25805 AN: 60374

GnomAD4 genome AF: 0.417 AC: 63375 AN: 151986 Hom.: 13664 Cov.: 31 AF XY: 0.420 AC XY: 31191 AN XY: 74258

African (AFR) AF: 0.364 AC: 15122 AN: 41490

American (AMR) AF: 0.425 AC: 6493 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1542 AN: 3466

East Asian (EAS) AF: 0.681 AC: 3491 AN: 5128

South Asian (SAS) AF: 0.426 AC: 2051 AN: 4812

European-Finnish (FIN) AF: 0.476 AC: 5018 AN: 10550

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28300 AN: 67956

Other (OTH) AF: 0.405 AC: 858 AN: 2116

Alfa AF: 0.411 Hom.: 35694

Bravo AF: 0.424

EpiCase AF: 0.404

EpiControl AF: 0.403

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.8
DANN	Benign	0.64
PhyloP100		0.25
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs861424; hg19: chr16-21078693; COSMIC: COSV54504313; COSMIC: COSV54504313;