5-13886135-CAAAAAAAAAA-CAAAAAA

Position:

• chr5-13886135-CAAAAAAAAAA-CAAAAAA

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000251423 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 402730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13886135-CAAAA-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2578-10_2578-7delTTTT		splice_region_variant, intron_variant		ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2578-10_2578-7delTTTT		splice_region_variant, intron_variant		1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2533-10_2533-7delTTTT		splice_region_variant, intron_variant				ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10438_254-10435delAAAA		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.214-10438_214-10435delAAAA		intron_variant		5

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

GnomAD3 exomes AF: 0.0300 AC: 1847 AN: 61536 Hom.: 0 AF XY: 0.0287 AC XY: 900 AN XY: 31394

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 SAS exome AF: 0.0255

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

Gnomad4 AFR exome AF: 0.0387

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.00708

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.00641 AC: 794 AN: 123836 Hom.: 11 Cov.: 0 AF XY: 0.00678 AC XY: 398 AN XY: 58696

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.000664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000519

Gnomad4 FIN AF: 0.00284

Gnomad4 NFE AF: 0.000374

Gnomad4 OTH AF: 0.00361

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs71600031; hg19: chr5-13886244;