rs111539520

Variant names:

• chr16-20963418-C-T
• rs111539520
• NM_001347886.2:c.10328G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 10 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 -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 VariationId is 402725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347886.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.10328G>A	p.Arg3443Gln	missense	Exon 53 of 62	NP_001334815.1
	DNAH3	NM_017539.2		c.10466G>A	p.Arg3489Gln	missense	Exon 53 of 62	NP_060009.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	ENST00000698260.1	MANE Select	c.10328G>A	p.Arg3443Gln	missense	Exon 53 of 62	ENSP00000513632.1
	DNAH3	ENST00000261383.3	TSL:1	c.10466G>A	p.Arg3489Gln	missense	Exon 53 of 62	ENSP00000261383.3
	DNAH3	ENST00000685858.1		c.10508G>A	p.Arg3503Gln	missense	Exon 53 of 62	ENSP00000508756.1

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

GnomAD2 exomes AF: 0.0198 AC: 4984 AN: 251446 AF XY: 0.0195

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 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

African (AFR) AF: 0.00547 AC: 183 AN: 33480

American (AMR) AF: 0.0110 AC: 494 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00319 AC: 275 AN: 86258

European-Finnish (FIN) AF: 0.0110 AC: 590 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0438 AC: 48730 AN: 1112006

Other (OTH) AF: 0.0284 AC: 1713 AN: 60396

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

African (AFR) AF: 0.00792 AC: 329 AN: 41534

American (AMR) AF: 0.0164 AC: 250 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.00970 AC: 103 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2518 AN: 68000

Other (OTH) AF: 0.0252 AC: 53 AN: 2104

Alfa AF: 0.0315 Hom.: 312

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.3
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
Mutation Taster		=99/1	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: rs111539520; hg19: chr16-20974740; COSMIC: COSV107212310;