rs73036225

Positions:

• chr7-756793-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017802.4(DNAAF5):​c.1269C>T​(p.Ser423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,080 control chromosomes in the GnomAD database, including 33,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2135 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31446 hom.)
• Consequence: DNAAF5 NM_017802.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.22

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-756793-C-T is Benign according to our data. Variant chr7-756793-C-T is described in ClinVar as [Benign]. Clinvar id is 260925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-756793-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1269C>T	p.Ser423=	synonymous_variant	6/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1269C>T	p.Ser423=	synonymous_variant	6/12
DNAAF5	NR_075098.2	n.1229C>T		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1269C>T	p.Ser423=	synonymous_variant	6/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.675C>T	p.Ser225=	synonymous_variant	6/13	2
DNAAF5	ENST00000437419.5			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21894 AN: 152152 Hom.: 2138 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.172

GnomAD3 exomes AF: 0.162 AC: 40769 AN: 251052 Hom.: 4116 AF XY: 0.172 AC XY: 23319 AN XY: 135792

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.200 AC: 292268 AN: 1460810 Hom.: 31446 Cov.: 34 AF XY: 0.201 AC XY: 146049 AN XY: 726718

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.0997

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.144 AC: 21888 AN: 152270 Hom.: 2135 Cov.: 33 AF XY: 0.139 AC XY: 10364 AN XY: 74454

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.170

Alfa AF: 0.193 Hom.: 1568

Bravo AF: 0.142

Asia WGS AF: 0.0710 AC: 247 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2016	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.28
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs73036225; hg19: chr7-796430;