rs76229167

Positions:

• chr5-13886024-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.2683G>A​(p.Glu895Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,612,148 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.05

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002672851).
• BP6: Variant 5-13886024-C-T is Benign according to our data. Variant chr5-13886024-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13886024-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2683G>A	p.Glu895Lys	missense_variant	18/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2683G>A	p.Glu895Lys	missense_variant	18/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2638G>A	p.Glu880Lys	missense_variant	18/79			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10565C>T		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.214-10565C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2313 AN: 151182 Hom.: 64 Cov.: 31

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00907

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00415 AC: 1041 AN: 250768 Hom.: 26 AF XY: 0.00325 AC XY: 440 AN XY: 135566

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00178 AC: 2594 AN: 1460846 Hom.: 72 Cov.: 32 AF XY: 0.00153 AC XY: 1110 AN XY: 726704

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000157

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.0154 AC: 2327 AN: 151302 Hom.: 64 Cov.: 31 AF XY: 0.0151 AC XY: 1114 AN XY: 73874

Gnomad4 AFR AF: 0.0519

Gnomad4 AMR AF: 0.00906

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0129

Alfa AF: 0.00283 Hom.: 9

Bravo AF: 0.0177

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00490 AC: 595

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary ciliary dyskinesia 3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2023	- -
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 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	Glu895Lys in exon 18 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 4.6% (203/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs76229167). -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.8
DANN	Benign	0.46
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.29	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.016
Sift	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.24
MPC		0.11
ClinPred		0.0017	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.16

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: rs76229167; hg19: chr5-13886133; COSMIC: COSV54226740;