rs6554827

Variant names:

• chr5-13864619-C-A
• rs6554827
• NM_001369.3:c.4374G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.4374G>T​(p.Arg1458Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,476 control chromosomes in the GnomAD database, including 151,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12231 hom., cov: 32)
  • Exomes 𝑓: 0.43 (139070 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.676
• Publications: 17 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5-AS1 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-13864619-C-A is Benign according to our data. Variant chr5-13864619-C-A is described in ClinVar as Benign. ClinVar VariationId is 178750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.676 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.4374G>T	p.Arg1458Arg	synonymous	Exon 28 of 79	NP_001360.1	Q8TE73
	DNAH5-AS1	NR_199035.1		n.117+4064C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.4374G>T	p.Arg1458Arg	synonymous	Exon 28 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.4329G>T	p.Arg1443Arg	synonymous	Exon 28 of 79	ENSP00000505288.1	A0A7P0Z455
	DNAH5-AS1	ENST00000503244.2	TSL:4	n.253+4064C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60025 AN: 151834 Hom.: 12213 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.401

GnomAD2 exomes AF: 0.402 AC: 100972 AN: 251218 AF XY: 0.410

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.433 AC: 632584 AN: 1461524 Hom.: 139070 Cov.: 46 AF XY: 0.434 AC XY: 315392 AN XY: 727084

African (AFR) AF: 0.320 AC: 10715 AN: 33470

American (AMR) AF: 0.301 AC: 13477 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9368 AN: 26128

East Asian (EAS) AF: 0.258 AC: 10256 AN: 39690

South Asian (SAS) AF: 0.468 AC: 40398 AN: 86248

European-Finnish (FIN) AF: 0.478 AC: 25521 AN: 53416

Middle Eastern (MID) AF: 0.348 AC: 2009 AN: 5766

European-Non Finnish (NFE) AF: 0.446 AC: 495704 AN: 1111704

Other (OTH) AF: 0.416 AC: 25136 AN: 60386

GnomAD4 genome AF: 0.395 AC: 60087 AN: 151952 Hom.: 12231 Cov.: 32 AF XY: 0.394 AC XY: 29272 AN XY: 74252

African (AFR) AF: 0.317 AC: 13139 AN: 41442

American (AMR) AF: 0.342 AC: 5215 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1236 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1343 AN: 5162

South Asian (SAS) AF: 0.465 AC: 2235 AN: 4806

European-Finnish (FIN) AF: 0.486 AC: 5124 AN: 10540

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30544 AN: 67956

Other (OTH) AF: 0.404 AC: 851 AN: 2106

Alfa AF: 0.421 Hom.: 21709

Bravo AF: 0.375

Asia WGS AF: 0.381 AC: 1327 AN: 3476

EpiCase AF: 0.431

EpiControl AF: 0.430

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.1
DANN	Benign	0.79
PhyloP100		-0.68
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: rs6554827; hg19: chr5-13864728; COSMIC: COSV54212419;