rs143045012

chr7-740825-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_017802.4(DNAAF5):c.787C>T(p.Arg263Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,750 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. R263Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.19

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011836708).
• BP6: Variant 7-740825-C-T is Benign according to our data. Variant chr7-740825-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 525551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000341 (52/152366) while in subpopulation EAS AF= 0.00809 (42/5190). AF 95% confidence interval is 0.00615. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.787C>T	p.Arg263Trp	missense_variant	3/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.787C>T	p.Arg263Trp	missense_variant	3/12
DNAAF5	NR_075098.2	n.747C>T		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.787C>T	p.Arg263Trp	missense_variant	3/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.193C>T	p.Arg65Trp	missense_variant	3/13	2
DNAAF5	ENST00000437419.5	c.106C>T	p.Arg36Trp	missense_variant	2/5	5
DNAAF5	ENST00000438961.1	n.256C>T		non_coding_transcript_exon_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000434 AC: 109 AN: 251060 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135726

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00528

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000321 AC: 469 AN: 1461384 Hom.: 2 Cov.: 32 AF XY: 0.000283 AC XY: 206 AN XY: 727062

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74512

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00809

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000370 Hom.: 2

Bravo AF: 0.000332

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 30, 2021

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2021

- -

DNAAF5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.044
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.16	T
Polyphen		0.92	P
Vest4		0.33
MVP		0.16
MPC		0.38
ClinPred		0.032	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.072
gMVP		0.33

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: rs143045012; hg19: chr7-780462; COSMIC: COSV52422878;