rs118139460

Positions:

• chr7-756956-G-A
• chr7-756956-G-C

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.1432G>A​(p.Glu478Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,606,914 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (3 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.96

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=0.0068619847).
• BP6: Variant 7-756956-G-A is Benign according to our data. Variant chr7-756956-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 454853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-756956-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00205 (313/152328) while in subpopulation AMR AF= 0.00379 (58/15310). AF 95% confidence interval is 0.00301. There are 3 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1432G>A	p.Glu478Lys	missense_variant	6/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1432G>A	p.Glu478Lys	missense_variant	6/12
DNAAF5	NR_075098.2	n.1392G>A		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1432G>A	p.Glu478Lys	missense_variant	6/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.838G>A	p.Glu280Lys	missense_variant	6/13	2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00101 AC: 247 AN: 245224 Hom.: 1 AF XY: 0.000894 AC XY: 119 AN XY: 133168

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.00247

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000715

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000755 AC: 1098 AN: 1454586 Hom.: 3 Cov.: 33 AF XY: 0.000720 AC XY: 521 AN XY: 723838

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000630

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00205 AC: 313 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74474

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00234

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000874 AC: 106

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 10, 2018	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 provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.089
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Polyphen		0.60	P
Vest4		0.33
MVP		0.048
MPC		0.21
ClinPred		0.0093	T
GERP RS		2.4
Varity_R		0.044
gMVP		0.35

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: rs118139460; hg19: chr7-796593;