rs73258248

chr7-763869-C-T

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.1678C>T(p.Arg560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 1,613,374 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. R560H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (32 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.548

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=0.006890416).
• BP6: Variant 7-763869-C-T is Benign according to our data. Variant chr7-763869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00509 (775/152360) while in subpopulation NFE AF= 0.00701 (477/68036). AF 95% confidence interval is 0.00649. There are 5 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1678C>T	p.Arg560Cys	missense_variant	8/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1678C>T	p.Arg560Cys	missense_variant	8/12
DNAAF5	NR_075098.2	n.1638C>T		non_coding_transcript_exon_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1678C>T	p.Arg560Cys	missense_variant	8/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.1084C>T	p.Arg362Cys	missense_variant	8/13	2
DNAAF5	ENST00000491496.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 775 AN: 152242 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00481 AC: 1207 AN: 250794 Hom.: 6 AF XY: 0.00487 AC XY: 661 AN XY: 135708

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00592 AC: 8644 AN: 1461014 Hom.: 32 Cov.: 32 AF XY: 0.00578 AC XY: 4200 AN XY: 726854

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00509 AC: 775 AN: 152360 Hom.: 5 Cov.: 33 AF XY: 0.00489 AC XY: 364 AN XY: 74512

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00701

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00594 Hom.: 6

Bravo AF: 0.00414

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00483 AC: 587

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00593

ClinVar

Significance: Benign/Likely 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 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

DNAAF5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.17
MPC		0.63
ClinPred		0.027	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.27

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: rs73258248; hg19: chr7-803506; COSMIC: COSV99859903; COSMIC: COSV99859903;