rs201264312

chr7-741410-C-Achr7-741410-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_017802.4(DNAAF5):c.969C>A(p.Asp323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,577,696 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.236

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009310216).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000354 (54/152378) while in subpopulation AMR AF= 0.00333 (51/15312). AF 95% confidence interval is 0.0026. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.969C>A	p.Asp323Glu	missense_variant	4/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.969C>A	p.Asp323Glu	missense_variant	4/12
DNAAF5	NR_075098.2	n.929C>A		non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.969C>A	p.Asp323Glu	missense_variant	4/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.375C>A	p.Asp125Glu	missense_variant	4/13	2
DNAAF5	ENST00000437419.5	c.288C>A	p.Asp96Glu	missense_variant	3/5	5
DNAAF5	ENST00000438961.1	n.438C>A		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000365 AC: 7 AN: 191912 Hom.: 0 AF XY: 0.0000294 AC XY: 3 AN XY: 101910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000401

GnomAD4 exome AF: 0.0000302 AC: 43 AN: 1425318 Hom.: 1 Cov.: 36 AF XY: 0.0000227 AC XY: 16 AN XY: 705192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000705

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000271

GnomAD4 genome AF: 0.000354 AC: 54 AN: 152378 Hom.: 0 Cov.: 34 AF XY: 0.000389 AC XY: 29 AN XY: 74514

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000839

ExAC AF: 0.00000838 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2022	The c.969C>A (p.D323E) alteration is located in exon 4 (coding exon 4) of the DNAAF5 gene. This alteration results from a C to A substitution at nucleotide position 969, causing the aspartic acid (D) at amino acid position 323 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 323 of the DNAAF5 protein (p.Asp323Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 454872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAAF5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Sift4G	Benign	0.27	T
Polyphen		0.67	P
Vest4		0.21
MutPred		0.22		Gain of methylation at K325 (P = 0.1224);
MVP		0.14
MPC		0.20
ClinPred		0.12	T
GERP RS		1.5
Varity_R		0.097
gMVP		0.43

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: rs201264312; hg19: chr7-781047;