5-13841918-CAAA-C

Variant names:

• chr5-13841918-CAAA-C
• rs35337694
• NM_001369.3:c.5272-17_5272-15delTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001369.3(DNAH5):​c.5272-17_5272-15delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 572,562 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 0)
  • Exomes 𝑓: 0.038 (2 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.617
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 5-13841918-CAAA-C is Benign according to our data. Variant chr5-13841918-CAAA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3076106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00231 (242/104624) while in subpopulation AFR AF = 0.0081 (228/28158). AF 95% confidence interval is 0.00724. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-17_5272-15delTTT		intron_variant	Intron 32 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.5272-17_5272-15delTTT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-17_5227-15delTTT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 241 AN: 104630 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00807

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000690

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000319

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000530

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000730

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.0380 AC: 17774 AN: 467938 Hom.: 2 AF XY: 0.0368 AC XY: 9308 AN XY: 252780

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

African (AFR) AF: 0.0890 AC: 1069 AN: 12008

American (AMR) AF: 0.0443 AC: 811 AN: 18322

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 487 AN: 13246

East Asian (EAS) AF: 0.0505 AC: 1298 AN: 25712

South Asian (SAS) AF: 0.0251 AC: 1077 AN: 42982

European-Finnish (FIN) AF: 0.0355 AC: 914 AN: 25762

Middle Eastern (MID) AF: 0.0361 AC: 69 AN: 1912

European-Non Finnish (NFE) AF: 0.0363 AC: 11020 AN: 303674

Other (OTH) AF: 0.0423 AC: 1029 AN: 24320

⚠️ 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: 0.00231 AC: 242 AN: 104624 Hom.: 1 Cov.: 0 AF XY: 0.00237 AC XY: 112 AN XY: 47244

African (AFR) AF: 0.00810 AC: 228 AN: 28158

American (AMR) AF: 0.000690 AC: 6 AN: 8696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2966

East Asian (EAS) AF: 0.000320 AC: 1 AN: 3122

South Asian (SAS) AF: 0.00 AC: 0 AN: 2694

European-Finnish (FIN) AF: 0.000530 AC: 1 AN: 1888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.0000730 AC: 4 AN: 54788

Other (OTH) AF: 0.00144 AC: 2 AN: 1392

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Aug 27, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35337694; hg19: chr5-13842027;