rs30168

Variant names:

• chr5-13718980-G-A
• rs30168
• NM_001369.3:c.12401C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-13718980-G-A
• chr5-13718980-G-C
• chr5-13718980-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.12401C>T​(p.Ala4134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,326 control chromosomes in the GnomAD database, including 144,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A4134A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.44 (15300 hom., cov: 31)
  • Exomes 𝑓: 0.42 (129276 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.04
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.029248E-5).
• BP6: Variant 5-13718980-G-A is Benign according to our data. Variant chr5-13718980-G-A is described in ClinVar as Benign. ClinVar VariationId is 178743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.12401C>T	p.Ala4134Val	missense_variant	Exon 72 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.12401C>T	p.Ala4134Val	missense_variant	Exon 72 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.12356C>T	p.Ala4119Val	missense_variant	Exon 72 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67323 AN: 151762 Hom.: 15268 Cov.: 31

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.440

GnomAD2 exomes AF: 0.425 AC: 106664 AN: 250980 AF XY: 0.424

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.411

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.419 AC: 611903 AN: 1461448 Hom.: 129276 Cov.: 43 AF XY: 0.419 AC XY: 304703 AN XY: 727076

African (AFR) AF: 0.534 AC: 17879 AN: 33476

American (AMR) AF: 0.445 AC: 19892 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10854 AN: 26132

East Asian (EAS) AF: 0.399 AC: 15850 AN: 39696

South Asian (SAS) AF: 0.455 AC: 39201 AN: 86246

European-Finnish (FIN) AF: 0.331 AC: 17691 AN: 53412

Middle Eastern (MID) AF: 0.456 AC: 2632 AN: 5766

European-Non Finnish (NFE) AF: 0.416 AC: 462118 AN: 1111624

Other (OTH) AF: 0.427 AC: 25786 AN: 60376

GnomAD4 genome AF: 0.444 AC: 67416 AN: 151878 Hom.: 15300 Cov.: 31 AF XY: 0.437 AC XY: 32442 AN XY: 74220

African (AFR) AF: 0.536 AC: 22185 AN: 41408

American (AMR) AF: 0.431 AC: 6580 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3472

East Asian (EAS) AF: 0.431 AC: 2208 AN: 5122

South Asian (SAS) AF: 0.451 AC: 2166 AN: 4802

European-Finnish (FIN) AF: 0.317 AC: 3342 AN: 10542

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27997 AN: 67948

Other (OTH) AF: 0.445 AC: 940 AN: 2112

Alfa AF: 0.424 Hom.: 53362

Bravo AF: 0.456

TwinsUK AF: 0.406 AC: 1504

ALSPAC AF: 0.403 AC: 1553

ESP6500AA AF: 0.535 AC: 2357

ESP6500EA AF: 0.425 AC: 3654

ExAC AF: 0.429 AC: 52057

Asia WGS AF: 0.469 AC: 1633 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.434

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala4134Val in exon 72 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 46.5% (2049/4406) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs30168). -

Primary ciliary dyskinesia Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 11, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.18
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.000040	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.093
ClinPred		0.00070	T
GERP RS		1.7
Varity_R		0.031
gMVP		0.17
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs30168; hg19: chr5-13719089; COSMIC: COSV54227221;