chr16-20987398-G-A

Variant names:

• chr16-20987398-G-A
• rs111770788
• NM_001347886.2:c.6795C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001347886.2(DNAH3):​c.6795C>T​(p.Phe2265Phe) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36
• Publications: 4 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 -19 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 VariationId is 402726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 65 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.6795C>T	p.Phe2265Phe	synonymous	Exon 47 of 62	NP_001334815.1	A0A8V8TLI9
	DNAH3	NM_017539.2		c.6933C>T	p.Phe2311Phe	synonymous	Exon 47 of 62	NP_060009.1	Q8TD57-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	ENST00000698260.1	MANE Select	c.6795C>T	p.Phe2265Phe	synonymous	Exon 47 of 62	ENSP00000513632.1	A0A8V8TLI9
	DNAH3	ENST00000261383.3	TSL:1	c.6933C>T	p.Phe2311Phe	synonymous	Exon 47 of 62	ENSP00000261383.3	Q8TD57-1
	DNAH3	ENST00000685858.1		c.6975C>T	p.Phe2325Phe	synonymous	Exon 47 of 62	ENSP00000508756.1	A0A8I5KSE2

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

GnomAD2 exomes AF: 0.0210 AC: 5276 AN: 251458 AF XY: 0.0208

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 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

African (AFR) AF: 0.00559 AC: 187 AN: 33480

American (AMR) AF: 0.0133 AC: 595 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00466 AC: 402 AN: 86258

European-Finnish (FIN) AF: 0.0121 AC: 649 AN: 53416

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0451 AC: 50169 AN: 1111984

Other (OTH) AF: 0.0304 AC: 1833 AN: 60394

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

African (AFR) AF: 0.00823 AC: 342 AN: 41552

American (AMR) AF: 0.0222 AC: 339 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0385 AC: 2618 AN: 68030

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

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

ClinVar submissions

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
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111770788; hg19: chr16-20998720; COSMIC: COSV107212311;