rs143185806

Variant names:

• chr5-13751149-T-C
• rs143185806
• NM_001369.3:c.11140A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001369.3(DNAH5):​c.11140A>G​(p.Ile3714Val) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (1 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.85
• Publications: 2 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02066961).
• BP6: Variant 5-13751149-T-C is Benign according to our data. Variant chr5-13751149-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552084.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.11140A>G	p.Ile3714Val	missense	Exon 65 of 79	NP_001360.1	Q8TE73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.11140A>G	p.Ile3714Val	missense	Exon 65 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.11095A>G	p.Ile3699Val	missense	Exon 65 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00143

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251268 AF XY: 0.000110

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461738 Hom.: 1 Cov.: 31 AF XY: 0.0000908 AC XY: 66 AN XY: 727184

African (AFR) AF: 0.00206 AC: 69 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111916

Other (OTH) AF: 0.000199 AC: 12 AN: 60386

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74452

African (AFR) AF: 0.00241 AC: 100 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.000786

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia (2)
-	2	-	Primary ciliary dyskinesia 3 (2)
-	1	-	DNAH5-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.096
Sift	Benign	0.12	T
Polyphen		0.056	B
Vest4		0.30
MVP		0.56
MPC		0.10
ClinPred		0.031	T
GERP RS		1.7
Varity_R		0.11
gMVP		0.41
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143185806; hg19: chr5-13751258; COSMIC: COSV99444300;