5-13718913-T-G

Position:

• chr5-13718913-T-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.12468A>C​(p.Gly4156Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,612,042 control chromosomes in the GnomAD database, including 138,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12470 hom., cov: 32)
  • Exomes 𝑓: 0.41 (126278 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0460

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=-0.51).
• BP6: Variant 5-13718913-T-G is Benign according to our data. Variant chr5-13718913-T-G is described in ClinVar as [Benign]. Clinvar id is 178742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13718913-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.046 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.12468A>C	p.Gly4156Gly	synonymous_variant	72/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.12468A>C	p.Gly4156Gly	synonymous_variant	72/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.12423A>C	p.Gly4141Gly	synonymous_variant	72/79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61243 AN: 151888 Hom.: 12452 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.404

GnomAD3 exomes AF: 0.414 AC: 103983 AN: 251176 Hom.: 21831 AF XY: 0.416 AC XY: 56484 AN XY: 135736

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.442

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.414 AC: 604683 AN: 1460036 Hom.: 126278 Cov.: 41 AF XY: 0.415 AC XY: 301515 AN XY: 726432

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.403 AC: 61311 AN: 152006 Hom.: 12470 Cov.: 32 AF XY: 0.398 AC XY: 29576 AN XY: 74286

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.407

Alfa AF: 0.415 Hom.: 17047

Bravo AF: 0.410

Asia WGS AF: 0.447 AC: 1558 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.433

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gly4156Gly in exon 72 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 42.4% (3649/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs30169). -

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.65

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: rs30169; hg19: chr5-13719022; COSMIC: COSV54212375;