chr5-13786242-C-G

Position:

• chr5-13786242-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000265104.5(DNAH5):​c.8757G>C​(p.Glu2919Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,614,082 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2919E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: DNAH5 ENST00000265104.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.109

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074081123).
• BP6: Variant 5-13786242-C-G is Benign according to our data. Variant chr5-13786242-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188365.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00416 (6080/1461778) while in subpopulation NFE AF= 0.00466 (5179/1111978). AF 95% confidence interval is 0.00455. There are 18 homozygotes in gnomad4_exome. There are 3004 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.8757G>C	p.Glu2919Asp	missense_variant	52/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.8757G>C	p.Glu2919Asp	missense_variant	52/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1	c.8712G>C	p.Glu2904Asp	missense_variant	52/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00309 AC: 776 AN: 250966 Hom.: 3 AF XY: 0.00320 AC XY: 434 AN XY: 135638

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.00629

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00416 AC: 6080 AN: 1461778 Hom.: 18 Cov.: 32 AF XY: 0.00413 AC XY: 3004 AN XY: 727188

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00300

Gnomad4 FIN exome AF: 0.00768

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00260 AC: 396 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74476

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00358 Hom.: 0

Bravo AF: 0.00226

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00349 AC: 424

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary ciliary dyskinesia 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 28, 2019	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2014	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

DNAH5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.072	T
Polyphen		0.19	B
Vest4		0.44
MutPred		0.29		Loss of helix (P = 0.1299);
MVP		0.56
MPC		0.25
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.24
gMVP		0.50

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: rs115776799; hg19: chr5-13786351;