5-13886135-CAAAAAAAAAA-CAAAAAAA

Variant names:

• chr5-13886135-CAAA-C
• rs71600031
• NM_001369.3:c.2578-9_2578-7delTTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001369.3(DNAH5):​c.2578-9_2578-7delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,297,624 control chromosomes in the GnomAD database, including 4,081 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (2646 hom., cov: 0)
  • Exomes 𝑓: 0.22 (1435 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.52
• Publications: 2 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 -9 ACMG points.

• BP6: Variant 5-13886135-CAAA-C is Benign according to our data. Variant chr5-13886135-CAAA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 351200.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.274 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.2578-9_2578-7delTTT		splice_region intron	N/A	NP_001360.1	Q8TE73
	DNAH5-AS1	NR_199035.1		n.118-10437_118-10435delAAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.2578-9_2578-7delTTT		splice_region intron	N/A	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.2533-9_2533-7delTTT		splice_region intron	N/A	ENSP00000505288.1	A0A7P0Z455
	DNAH5-AS1	ENST00000503244.2	TSL:4	n.254-10453_254-10451delAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.213 AC: 26373 AN: 123808 Hom.: 2647 Cov.: 0

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.206 AC: 12664 AN: 61536 AF XY: 0.197

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0888

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.220 AC: 257846 AN: 1173838 Hom.: 1435 AF XY: 0.219 AC XY: 126977 AN XY: 579636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.173 AC: 4453 AN: 25694

American (AMR) AF: 0.264 AC: 6869 AN: 26062

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 4563 AN: 19922

East Asian (EAS) AF: 0.0664 AC: 2072 AN: 31190

South Asian (SAS) AF: 0.202 AC: 12574 AN: 62108

European-Finnish (FIN) AF: 0.213 AC: 6391 AN: 29974

Middle Eastern (MID) AF: 0.247 AC: 840 AN: 3404

European-Non Finnish (NFE) AF: 0.226 AC: 209449 AN: 926556

Other (OTH) AF: 0.217 AC: 10635 AN: 48928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.213 AC: 26357 AN: 123786 Hom.: 2646 Cov.: 0 AF XY: 0.214 AC XY: 12587 AN XY: 58684

African (AFR) AF: 0.149 AC: 5038 AN: 33782

American (AMR) AF: 0.282 AC: 3397 AN: 12042

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 847 AN: 3004

East Asian (EAS) AF: 0.0620 AC: 222 AN: 3582

South Asian (SAS) AF: 0.215 AC: 825 AN: 3844

European-Finnish (FIN) AF: 0.250 AC: 1497 AN: 5994

Middle Eastern (MID) AF: 0.292 AC: 69 AN: 236

European-Non Finnish (NFE) AF: 0.236 AC: 13864 AN: 58834

Other (OTH) AF: 0.221 AC: 366 AN: 1658

Alfa AF: 0.0927 Hom.: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Primary ciliary dyskinesia (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	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: rs71600031; hg19: chr5-13886244;