rs199680570

chr16-84176224-A-Cchr16-84176224-A-G

Variant summary

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

The NM_178452.6(DNAAF1):c.1990A>C(p.Thr664Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T664S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.320

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

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=0.036447793).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00027 (41/152078) while in subpopulation AFR AF= 0.000966 (40/41408). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 22 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
DNAAF1	NM_178452.6	c.1990A>C	p.Thr664Pro	missense_variant	11/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1990A>C	p.Thr664Pro	missense_variant	11/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000799 AC: 20 AN: 250294 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135616

Gnomad AFR exome AF: 0.000623

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461254 Hom.: 0 Cov.: 51 AF XY: 0.0000110 AC XY: 8 AN XY: 726958

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000568

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74290

Gnomad4 AFR AF: 0.000966

Gnomad4 AMR AF: 0.00

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: 0.000478

Alfa AF: 0.0000999 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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	Dec 09, 2023	The c.1990A>C (p.T664P) alteration is located in exon 11 (coding exon 11) of the DNAAF1 gene. This alteration results from a A to C substitution at nucleotide position 1990, causing the threonine (T) at amino acid position 664 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 664 of the DNAAF1 protein (p.Thr664Pro). 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 DNAAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 455003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Thr664Pro var iant in DNAAF1 has not been previously reported in individuals with pulmonary di sease but has been identified in 0.1% (12/8722) of African chromosomes by the Ge nome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199 680570). This variant has also been reported in ClinVar (Variation ID 455003). C omputational prediction tools and conservation analysis suggest that the p.Thr66 4Pro variant may not impact the protein, though this information is not predicti ve enough to rule out pathogenicity. In summary, while the clinical significance of the p.Thr664Pro variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.2
Dann	Benign	0.90
DEOGEN2	Benign	0.0070	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.071
Sift	Uncertain	0.0080	D;T
Sift4G	Uncertain	0.015	D;T
Polyphen		0.011	B;.
Vest4		0.20
MVP		0.072
MPC		0.022
ClinPred		0.027	T
GERP RS		-9.1
Varity_R		0.21
gMVP		0.080

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: rs199680570; hg19: chr16-84209830;