rs145457535

Variant names:

• chr17-44902549-A-C
• rs145457535
• NM_213607.3:c.461A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-44902549-A-C
• chr17-44902549-A-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_213607.3(DNAAF19):​c.461A>C​(p.His154Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000803497: Well-established functional studies show a deleterious effect (PMID:28790179) (PMID:22581229)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H154H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: DNAAF19 NM_213607.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 U:1
• Conservation: PhyloP100: 4.28
• Publications: 27 publications found

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF19 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 17

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000803497: Well-established functional studies show a deleterious effect (PMID:28790179) (PMID:22581229).; SCV000914770: "In vivo functional studies in zebrafish demonstrated that the p.His154Pro variant mRNA could not rescue a mutant phenotype, while the wild type CCDC103 mRNA was able to rescue the mutant phenotype, demonstrating a lack of function of the p.His154Pro variant protein (Panizzi et al. 2012)."; SCV004171960: Functional studies have demonstrated a lack of function of the p.His154Pro variant protein (Panizzi JR, et. al.,2012;Shoemark A, et. al.,2018).; SCV000291913: Experimental studies have shown that this missense change affects CCDC103 function (PMID: 22581229).; SCV000967657: Functional studies provide some evidence that the p.His154Pro variant may reduce protein function (Panizzi 2012).; SCV002633390: Injection of the mutant mRNA in smh zebrafish partially rescued the phenotype, suggesting that this may be a hypomorphic variant (Panizzi JR et al. Nat. Genet., 2012 May;44:714-9). In addition, biochemical analysis has shown that the H154P alteration is highly disruptive of oligomerization ability, although mutant protein retains the ability to dimerize (Shoemark A et al. Thorax, 2018 02;73:157-166).; SCV001983134: Published functional studies in zebra fish suggest a damaging effect with partial rescue of axis curvature or cilia motility phenotypes. In addition, reduced cilia beat amplitude or loss of beat coordination and cilia paralysis was observed in respiratory cells from patients homozygous for this variant (Panizzi et al,. 2012)
• PP5: Variant 17-44902549-A-C is Pathogenic according to our data. Variant chr17-44902549-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019673496). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. 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
	DNAAF19	NM_213607.3	MANE Select	c.461A>C	p.His154Pro	missense	Exon 4 of 4	NP_998772.1	Q8IW40-1
	DNAAF19	NM_001258395.2		c.461A>C	p.His154Pro	missense	Exon 4 of 4	NP_001245324.1	Q8IW40-1
	DNAAF19	NM_001258396.2		c.461A>C	p.His154Pro	missense	Exon 4 of 4	NP_001245325.1	Q8IW40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.461A>C	p.His154Pro	missense	Exon 4 of 4	ENSP00000391692.2	Q8IW40-1
	DNAAF19	ENST00000410006.6	TSL:2	c.461A>C	p.His154Pro	missense	Exon 4 of 4	ENSP00000387252.1	Q8IW40-1
	DNAAF19	ENST00000357776.6	TSL:2	c.461A>C	p.His154Pro	missense	Exon 4 of 4	ENSP00000350420.2	F8W6J8

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 300 AN: 251310 AF XY: 0.00136

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00188 AC: 2753 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.00193 AC XY: 1405 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00304 AC: 262 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00212 AC: 2356 AN: 1112012

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74498

African (AFR) AF: 0.000385 AC: 16 AN: 41578

American (AMR) AF: 0.000849 AC: 13 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00148 Hom.: 4

Bravo AF: 0.00117

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Primary ciliary dyskinesia 17 (14)
5	-	-	Primary ciliary dyskinesia (5)
3	-	-	not provided (3)
1	-	-	CCDC103-related disorder (1)
1	-	-	Hereditary spastic paraplegia 50 (1)
-	1	-	Infertility disorder (1)
1	-	-	Respiratory ciliopathies including non-CF bronchiectasis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.24
Sift	Benign	0.053	T
Sift4G	Benign	0.18	T
Polyphen		0.93	P
Vest4		0.68
MVP		0.66
MPC		0.77
ClinPred		0.79	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.72
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs145457535; hg19: chr17-42979917;