16-84145472-G-C

Variant names:

• chr16-84145472-G-C
• rs1441002883
• NM_178452.6:c.32G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178452.6(DNAAF1):​c.32G>C​(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,784 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.310

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0537571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 12	1	NM_178452.6	ENSP00000367815.5
DNAAF1	ENST00000567918.5	n.32G>C		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000455154.1
DNAAF1	ENST00000563093.5	n.32G>C		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000457373.1
DNAAF1	ENST00000570298.5	n.186G>C		non_coding_transcript_exon_variant	Exon 1 of 11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425784 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 11 of the DNAAF1 protein (p.Gly11Ala). This variant is not present in population databases (gnomAD no frequency). 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: 525263). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.060
Sift	Benign	0.054	T
Sift4G	Benign	0.15	T
Polyphen		0.058	B
Vest4		0.087
MutPred		0.063		Gain of glycosylation at P8 (P = 0.0867);
MVP		0.030
MPC		0.029
ClinPred		0.068	T
GERP RS		0.85
Varity_R		0.045
gMVP		0.23

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: rs1441002883; hg19: chr16-84179077;