rs1060502832

Variant names:

• chr19-55161821-C-A
• rs1060502832
• NM_001256715.2:c.485G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-55161821-C-A
• chr19-55161821-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001256715.2(DNAAF3):​c.485G>T​(p.Arg162Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000078 in 1,282,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R162S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 1 publications found

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.485G>T	p.Arg162Leu	missense_variant	Exon 6 of 12	ENST00000524407.7	NP_001243644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.485G>T	p.Arg162Leu	missense_variant	Exon 6 of 12	1	NM_001256715.2	ENSP00000432046.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1282656 Hom.: 0 Cov.: 32 AF XY: 0.00000160 AC XY: 1 AN XY: 623062

African (AFR) AF: 0.00 AC: 0 AN: 26758

American (AMR) AF: 0.00 AC: 0 AN: 21668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18994

East Asian (EAS) AF: 0.00 AC: 0 AN: 32200

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 65062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1027796

Other (OTH) AF: 0.00 AC: 0 AN: 53078

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Mar 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 230 of the DNAAF3 protein (p.Arg230Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a DNAAF3-related disease. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	.;M;.;.
PhyloP100		2.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	D;.;.;D
REVEL	Benign	0.20
Sift	Benign	0.061	T;.;.;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.60
MutPred		0.34		.;Loss of MoRF binding (P = 0.0402);.;.;
MVP		0.33
MPC		1.9
ClinPred		0.93	D
GERP RS		3.7
Varity_R		0.16
gMVP		0.73
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1060502832; hg19: chr19-55673189;