chr5-13841918-C-CAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001369.3(DNAH5):​c.5272-17_5272-15dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00802 (839/104582) while in subpopulation AFR AF = 0.0278 (783/28116). AF 95% confidence interval is 0.0262. There are 12 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-17_5272-15dupTTT		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.5272-15_5272-14insTTT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-15_5227-14insTTT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 838 AN: 104588 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00319

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.000529

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000274

Gnomad OTH AF: 0.00360

GnomAD4 exome AF: 0.00192 AC: 937 AN: 487352 Hom.: 0 Cov.: 0 AF XY: 0.00194 AC XY: 512 AN XY: 263412

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

African (AFR) AF: 0.00640 AC: 80 AN: 12506

American (AMR) AF: 0.00224 AC: 43 AN: 19166

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 14 AN: 13854

East Asian (EAS) AF: 0.00551 AC: 149 AN: 27028

South Asian (SAS) AF: 0.00347 AC: 156 AN: 44982

European-Finnish (FIN) AF: 0.00232 AC: 62 AN: 26734

Middle Eastern (MID) AF: 0.000503 AC: 1 AN: 1988

European-Non Finnish (NFE) AF: 0.00121 AC: 382 AN: 315748

Other (OTH) AF: 0.00197 AC: 50 AN: 25346

⚠️ 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: 0.00802 AC: 839 AN: 104582 Hom.: 12 Cov.: 0 AF XY: 0.00838 AC XY: 396 AN XY: 47228

African (AFR) AF: 0.0278 AC: 783 AN: 28116

American (AMR) AF: 0.00276 AC: 24 AN: 8696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2964

East Asian (EAS) AF: 0.00320 AC: 10 AN: 3122

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2694

European-Finnish (FIN) AF: 0.000529 AC: 1 AN: 1892

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

European-Non Finnish (NFE) AF: 0.000274 AC: 15 AN: 54786

Other (OTH) AF: 0.00359 AC: 5 AN: 1392

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35337694; hg19: chr5-13842027;