chr7-763869-C-T

Variant names:

• chr7-763869-C-T
• rs73258248
• NM_017802.4:c.1678C>T

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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:5
• Conservation: PhyloP100: 0.548
• Publications: 9 publications found

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]

DNAAF5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 18

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. 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
	DNAAF5	NM_017802.4	MANE Select	c.1678C>T	p.Arg560Cys	missense	Exon 8 of 13	NP_060272.3
	DNAAF5	NR_075098.2		n.1638C>T		non_coding_transcript_exon	Exon 8 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.1678C>T	p.Arg560Cys	missense	Exon 8 of 13	ENSP00000297440.6
	DNAAF5	ENST00000440747.5	TSL:2	c.1081C>T	p.Arg361Cys	missense	Exon 8 of 13	ENSP00000403165.1
	DNAAF5	ENST00000491496.1	TSL:2	n.-38C>T		upstream_gene	N/A

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

GnomAD2 exomes AF: 0.00481 AC: 1207 AN: 250794 AF XY: 0.00487

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 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

African (AFR) AF: 0.00179 AC: 60 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00173 AC: 149 AN: 86258

European-Finnish (FIN) AF: 0.0134 AC: 702 AN: 52566

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00667 AC: 7413 AN: 1112002

Other (OTH) AF: 0.00414 AC: 250 AN: 60382

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

African (AFR) AF: 0.00226 AC: 94 AN: 41588

American (AMR) AF: 0.00248 AC: 38 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00701 AC: 477 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00564 Hom.: 7

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

May 20, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAAF5: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.55
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
Mutation Taster		=100/0	polymorphism

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