rs148720124

chr5-13793948-C-Achr5-13793948-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001369.3(DNAH5):c.7998G>T(p.Glu2666Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,962 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. E2666E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (16 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: -0.706

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050961107).
• BP6: Variant 5-13793948-C-A is Benign according to our data. Variant chr5-13793948-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188229.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=5}. Variant chr5-13793948-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.7998G>T	p.Glu2666Asp	missense_variant	48/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.7998G>T	p.Glu2666Asp	missense_variant	48/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.7953G>T	p.Glu2651Asp	missense_variant	48/79			A1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00122 AC: 307 AN: 250870 Hom.: 2 AF XY: 0.00121 AC XY: 164 AN XY: 135564

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00234 AC: 3424 AN: 1461676 Hom.: 16 Cov.: 32 AF XY: 0.00235 AC XY: 1708 AN XY: 727156

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74466

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00186 Hom.: 0

Bravo AF: 0.00124

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00123 AC: 149

EpiCase AF: 0.00224

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary ciliary dyskinesia Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2021	This alteration is classified as likely 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	Invitae	Jan 31, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2016	The E2666D variant in the DNAH5 gene has been reported previously in the heterozygous state in one individual with idiopathic, non-syndromic reduced sperm motility (Zuccarello et al., 2008). While not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports E2666D was observed in 22/8600 (0.25%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The E2666D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E2666D as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Glu2666Asp va riant in DNAH5 has been reported in 1 heterozygous Caucasian individual with iso lated asthenozoospermia (Zuccarello 2008). It has also been identified in 0.2% ( 115/66240) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs148720124). Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, while the clinical significance of the p.Glu2666As p variant is uncertain, its frequency suggests that it is more likely to be beni gn. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Benign	0.084	T
Polyphen		0.61	P
Vest4		0.74
MutPred		0.38		Loss of helix (P = 0.0558);
MVP		0.43
MPC		0.25
ClinPred		0.19	T
GERP RS		-1.8
Varity_R		0.35
gMVP		0.41

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: rs148720124; hg19: chr5-13794057;