rs148116155

chr19-55165408-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001256715.2(DNAAF3):c.284G>A(p.Ser95Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46

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

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010268629).
• BP6: Variant 19-55165408-C-T is Benign according to our data. Variant chr19-55165408-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000801 (122/152302) while in subpopulation AFR AF= 0.00277 (115/41570). AF 95% confidence interval is 0.00236. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.284G>A	p.Ser95Asn	missense_variant	4/12	ENST00000524407.7
DNAAF3-AS1	XR_007067344.1	n.357-411C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.284G>A	p.Ser95Asn	missense_variant	4/12	1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.1186+2607C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000228 AC: 57 AN: 249578 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135406

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.000203

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: 0.000165

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43 AN XY: 727242

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.000201

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: 0.000149

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.000658 AC XY: 49 AN XY: 74468

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000910

ESP6500AA AF: 0.00309 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000372 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2021	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	20
Dann	Uncertain	0.97
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.61	T;T;T;T;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.78	N;.;.;N;.;.;.
REVEL	Benign	0.039
Sift	Benign	0.39	T;.;.;T;.;.;.
Sift4G	Benign	0.23	T;T;T;T;T;.;.
Polyphen		0.18	.;B;.;.;.;.;.
Vest4		0.30
MVP		0.26
MPC		0.47
ClinPred		0.0064	T
GERP RS		2.4
Varity_R		0.065
gMVP		0.58

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: rs148116155; hg19: chr19-55676776;