rs200894344

chr5-13721175-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001369.3(DNAH5):c.12104C>T(p.Thr4035Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,076 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T4035T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.23

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 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=0.059306473).
• BP6: Variant 5-13721175-G-A is Benign according to our data. Variant chr5-13721175-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 454734.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.12104C>T	p.Thr4035Met	missense_variant	71/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.12104C>T	p.Thr4035Met	missense_variant	71/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.12059C>T	p.Thr4020Met	missense_variant	71/79			A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251356 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135846

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000218 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 10, 2022	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2023	- -

Primary ciliary dyskinesia 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	17
Dann	Benign	0.44
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.16	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.045
Sift	Benign	0.55	T
Polyphen		0.0030	B
Vest4		0.33
MutPred		0.43		Loss of ubiquitination at K4034 (P = 0.0768);
MVP		0.28
MPC		0.098
ClinPred		0.020	T
GERP RS		2.6
Varity_R		0.052
gMVP		0.73

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: rs200894344; hg19: chr5-13721284; COSMIC: COSV54232968;