chr5-13780882-C-T

Variant names:

• chr5-13780882-C-T
• rs111995400
• NM_001369.3:c.8898G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001369.3(DNAH5):​c.8898G>A​(p.Thr2966Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,613,708 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2966T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (55 hom., cov: 32)
  • Exomes 𝑓: 0.028 (641 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.59
• Publications: 4 publications found

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-13780882-C-T is Benign according to our data. Variant chr5-13780882-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0226 (3441/152288) while in subpopulation NFE AF = 0.0308 (2092/68028). AF 95% confidence interval is 0.0297. There are 55 homozygotes in GnomAd4. There are 1755 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. 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
	DNAH5	NM_001369.3	MANE Select	c.8898G>A	p.Thr2966Thr	synonymous	Exon 53 of 79	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.8898G>A	p.Thr2966Thr	synonymous	Exon 53 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.8853G>A	p.Thr2951Thr	synonymous	Exon 53 of 79	ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3442 AN: 152170 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0241 AC: 6038 AN: 250834 AF XY: 0.0244

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0523

Gnomad NFE exome AF: 0.0319

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0284 AC: 41433 AN: 1461420 Hom.: 641 Cov.: 32 AF XY: 0.0276 AC XY: 20060 AN XY: 727012

African (AFR) AF: 0.00415 AC: 139 AN: 33456

American (AMR) AF: 0.0151 AC: 674 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 767 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00638 AC: 550 AN: 86250

European-Finnish (FIN) AF: 0.0492 AC: 2625 AN: 53394

Middle Eastern (MID) AF: 0.0255 AC: 147 AN: 5760

European-Non Finnish (NFE) AF: 0.0315 AC: 35062 AN: 1111722

Other (OTH) AF: 0.0243 AC: 1468 AN: 60358

GnomAD4 genome AF: 0.0226 AC: 3441 AN: 152288 Hom.: 55 Cov.: 32 AF XY: 0.0236 AC XY: 1755 AN XY: 74454

African (AFR) AF: 0.00527 AC: 219 AN: 41560

American (AMR) AF: 0.0202 AC: 309 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

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

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0544 AC: 577 AN: 10600

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0308 AC: 2092 AN: 68028

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0273 Hom.: 34

Bravo AF: 0.0196

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0321

EpiControl AF: 0.0322

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Primary ciliary dyskinesia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.53
DANN	Benign	0.78
PhyloP100		-2.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs111995400; hg19: chr5-13780991; COSMIC: COSV54225124;