NM_001369.3:c.5115-5T>C

Variant names:

• chr5-13844998-A-G
• rs4429853
• NM_001369.3:c.5115-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.5115-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,611,676 control chromosomes in the GnomAD database, including 108,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12597 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95899 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003832
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.128
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-13844998-A-G is Benign according to our data. Variant chr5-13844998-A-G is described in ClinVar as Benign. ClinVar VariationId is 163149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.5115-5T>C		splice_region intron	N/A	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.5115-5T>C		splice_region intron	N/A	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.5070-5T>C		splice_region intron	N/A	ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60853 AN: 151824 Hom.: 12578 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.398

GnomAD2 exomes AF: 0.379 AC: 94931 AN: 250624 AF XY: 0.372

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.359 AC: 524248 AN: 1459734 Hom.: 95899 Cov.: 36 AF XY: 0.358 AC XY: 259714 AN XY: 726308

African (AFR) AF: 0.497 AC: 16614 AN: 33418

American (AMR) AF: 0.369 AC: 16485 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 8849 AN: 26114

East Asian (EAS) AF: 0.559 AC: 22168 AN: 39684

South Asian (SAS) AF: 0.339 AC: 29198 AN: 86216

European-Finnish (FIN) AF: 0.326 AC: 17415 AN: 53370

Middle Eastern (MID) AF: 0.305 AC: 1757 AN: 5758

European-Non Finnish (NFE) AF: 0.351 AC: 389436 AN: 1110188

Other (OTH) AF: 0.370 AC: 22326 AN: 60290

GnomAD4 genome AF: 0.401 AC: 60913 AN: 151942 Hom.: 12597 Cov.: 32 AF XY: 0.398 AC XY: 29538 AN XY: 74272

African (AFR) AF: 0.499 AC: 20652 AN: 41424

American (AMR) AF: 0.371 AC: 5671 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3128 AN: 5152

South Asian (SAS) AF: 0.346 AC: 1665 AN: 4806

European-Finnish (FIN) AF: 0.315 AC: 3327 AN: 10562

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23965 AN: 67944

Other (OTH) AF: 0.396 AC: 835 AN: 2108

Alfa AF: 0.368 Hom.: 5558

Bravo AF: 0.413

Asia WGS AF: 0.454 AC: 1576 AN: 3478

EpiCase AF: 0.349

EpiControl AF: 0.345

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.30
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.050		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: rs4429853; hg19: chr5-13845107;