rs113374052

Positions:

• chr7-741362-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017802.4(DNAAF5):​c.921C>A​(p.Ser307Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,588,566 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 34)
  • Exomes 𝑓: 0.015 (206 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0540

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004960537).
• BP6: Variant 7-741362-C-A is Benign according to our data. Variant chr7-741362-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 241211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-741362-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2006/152338) while in subpopulation NFE AF= 0.0199 (1352/68030). AF 95% confidence interval is 0.019. There are 23 homozygotes in gnomad4. There are 1001 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.921C>A	p.Ser307Arg	missense_variant	4/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.921C>A	p.Ser307Arg	missense_variant	4/12
DNAAF5	NR_075098.2	n.881C>A		non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.921C>A	p.Ser307Arg	missense_variant	4/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.327C>A	p.Ser109Arg	missense_variant	4/13	2
DNAAF5	ENST00000437419.5	c.240C>A	p.Ser80Arg	missense_variant	3/5	5
DNAAF5	ENST00000438961.1	n.390C>A		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2006 AN: 152220 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0118 AC: 2495 AN: 211058 Hom.: 26 AF XY: 0.0116 AC XY: 1313 AN XY: 113112

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.0000630

Gnomad SAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.00840

GnomAD4 exome AF: 0.0148 AC: 21316 AN: 1436228 Hom.: 206 Cov.: 36 AF XY: 0.0146 AC XY: 10411 AN XY: 711832

Gnomad4 AFR exome AF: 0.00235

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.00771

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00347

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0132 AC: 2006 AN: 152338 Hom.: 23 Cov.: 34 AF XY: 0.0134 AC XY: 1001 AN XY: 74506

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00927

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0169 Hom.: 36

Bravo AF: 0.0106

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0107 AC: 1286

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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 19, 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

-

- -

Primary ciliary dyskinesia 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 23, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.076
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.34	B
Vest4		0.14
MutPred		0.29		Gain of MoRF binding (P = 0.3096);
MPC		0.24
ClinPred		0.0043	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.036
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs113374052; hg19: chr7-780999; COSMIC: COSV99033859;