chr5-13886135-CAAAA-C

Variant names:

• chr5-13886135-CAAAA-C
• rs71600031
• NM_001369.3:c.2578-10_2578-7delTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):​c.2578-10_2578-7delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,316,524 control chromosomes in the GnomAD database, including 14 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 0)
  • Exomes 𝑓: 0.025 (3 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251423 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-13886135-CAAAA-C is Benign according to our data. Variant chr5-13886135-CAAAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (794/123836) while in subpopulation AFR AF = 0.0211 (712/33796). AF 95% confidence interval is 0.0198. There are 11 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.2578-10_2578-7delTTTT		splice_region intron	N/A	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.118-10438_118-10435delAAAA		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.2578-10_2578-7delTTTT		splice_region intron	N/A	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.2533-10_2533-7delTTTT		splice_region intron	N/A	ENSP00000505288.1
	ENSG00000251423	ENST00000503244.2	TSL:4	n.254-10453_254-10450delAAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 793 AN: 123858 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.000664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000516

Gnomad FIN AF: 0.00284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000374

Gnomad OTH AF: 0.00362

GnomAD2 exomes AF: 0.0300 AC: 1847 AN: 61536 AF XY: 0.0287

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0501

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00728

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0265

GnomAD4 exome AF: 0.0254 AC: 30317 AN: 1192688 Hom.: 3 AF XY: 0.0250 AC XY: 14725 AN XY: 589490

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

African (AFR) AF: 0.0387 AC: 1014 AN: 26208

American (AMR) AF: 0.0389 AC: 1035 AN: 26638

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 586 AN: 20282

East Asian (EAS) AF: 0.00708 AC: 229 AN: 32364

South Asian (SAS) AF: 0.0229 AC: 1465 AN: 63918

European-Finnish (FIN) AF: 0.0259 AC: 791 AN: 30498

Middle Eastern (MID) AF: 0.0324 AC: 112 AN: 3460

European-Non Finnish (NFE) AF: 0.0253 AC: 23776 AN: 939654

Other (OTH) AF: 0.0264 AC: 1309 AN: 49666

⚠️ 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: 0.00641 AC: 794 AN: 123836 Hom.: 11 Cov.: 0 AF XY: 0.00678 AC XY: 398 AN XY: 58696

African (AFR) AF: 0.0211 AC: 712 AN: 33796

American (AMR) AF: 0.00274 AC: 33 AN: 12048

Ashkenazi Jewish (ASJ) AF: 0.000664 AC: 2 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.000519 AC: 2 AN: 3852

European-Finnish (FIN) AF: 0.00284 AC: 17 AN: 5982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000374 AC: 22 AN: 58852

Other (OTH) AF: 0.00361 AC: 6 AN: 1662

Alfa AF: 0.0119 Hom.: 15

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, No homozygotes in ExAC, but on the low side of coverage. Gene is associated with PCD.

Primary ciliary dyskinesia Benign:1

Sep 27, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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;