rs112217391

Positions:

chr5-13870826-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001369.3(DNAH5):c.3775G>A(p.Ala1259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1259V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.19

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0119665265).

BP6

Variant 5-13870826-C-T is Benign according to our data. Variant chr5-13870826-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195809.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr5-13870826-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.3775G>A	p.Ala1259Thr	missense_variant	24/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.3775G>A	p.Ala1259Thr	missense_variant	24/79	1	NM_001369.3	P4
	ENST00000503244.2 linkuse as main transcript	n.253+10271C>T		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.3730G>A	p.Ala1244Thr	missense_variant	24/79			A1
	ENST00000637153.1 linkuse as main transcript	n.213+10311C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000291

AC:

AN:

251068

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000102

AC:

149

AN:

1461592

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00341

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00112

AC:

171

AN:

152288

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2017	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.5

DANN

Benign

0.65

DEOGEN2

Benign

0.051

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

M_CAP

Benign

0.028

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.12

Sift

Benign

0.56

Polyphen

0.0080

Vest4

0.32

MVP

0.18

MPC

0.25

ClinPred

0.014

GERP RS

3.7

Varity_R

0.12

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over