NM_001369.3:c.4510G>C

Variant names:

• chr5-13864483-C-G
• rs143567667
• NM_001369.3:c.4510G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001369.3(DNAH5):​c.4510G>C​(p.Gly1504Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,614,126 control chromosomes in the GnomAD database, including 5 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. G1504G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.44
• Publications: 5 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

DNAH5-AS1 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012972176).
• BP6: Variant 5-13864483-C-G is Benign according to our data. Variant chr5-13864483-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227325.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (415/152278) while in subpopulation AFR AF = 0.00936 (389/41562). AF 95% confidence interval is 0.00859. There are 4 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.4510G>C	p.Gly1504Arg	missense	Exon 28 of 79	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.117+3928C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.4510G>C	p.Gly1504Arg	missense	Exon 28 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.4465G>C	p.Gly1489Arg	missense	Exon 28 of 79	ENSP00000505288.1
	DNAH5-AS1	ENST00000503244.2	TSL:4	n.253+3928C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152160 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000728 AC: 183 AN: 251360 AF XY: 0.000464

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461848 Hom.: 1 Cov.: 32 AF XY: 0.000308 AC XY: 224 AN XY: 727226

African (AFR) AF: 0.0103 AC: 345 AN: 33478

American (AMR) AF: 0.000783 AC: 35 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111992

Other (OTH) AF: 0.000944 AC: 57 AN: 60396

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74456

African (AFR) AF: 0.00936 AC: 389 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000209 Hom.: 1

Bravo AF: 0.00310

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not specified (2)
-	1	1	Primary ciliary dyskinesia 3 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.35
Sift	Benign	0.13	T
Polyphen		0.74	P
Vest4		0.43
MutPred		0.57		Gain of MoRF binding (P = 0.0155)
MVP		0.85
MPC		0.54
ClinPred		0.069	T
GERP RS		5.3
Varity_R		0.52
gMVP		0.62
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs143567667; hg19: chr5-13864592;