rs61744054

Positions:

• chr5-13716688-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.12708T>C​(p.Gly4236Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,609,210 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (126 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (163 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.35

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 5-13716688-A-G is Benign according to our data. Variant chr5-13716688-A-G is described in ClinVar as [Benign]. Clinvar id is 226592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13716688-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.12708T>C	p.Gly4236Gly	splice_region_variant, synonymous_variant	74/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.12708T>C	p.Gly4236Gly	splice_region_variant, synonymous_variant	74/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.12663T>C	p.Gly4221Gly	splice_region_variant, synonymous_variant	74/79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3663 AN: 152138 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00972 AC: 2434 AN: 250520 Hom.: 74 AF XY: 0.00871 AC XY: 1179 AN XY: 135414

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00443 AC: 6448 AN: 1456954 Hom.: 163 Cov.: 30 AF XY: 0.00446 AC XY: 3233 AN XY: 725228

Gnomad4 AFR exome AF: 0.0830

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00913

GnomAD4 genome AF: 0.0241 AC: 3668 AN: 152256 Hom.: 126 Cov.: 32 AF XY: 0.0242 AC XY: 1799 AN XY: 74464

Gnomad4 AFR AF: 0.0768

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0119 Hom.: 31

Bravo AF: 0.0287

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00303

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2015	This alteration is classified as 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. -

Primary ciliary dyskinesia 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gly4236Gly in exon 74 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 8.1% (355/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61744054). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0080
DANN	Benign	0.45

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: rs61744054; hg19: chr5-13716797;