NM_001256715.2:c.323-4delG

Variant names:

• chr19-55162293-AC-A
• rs201986299
• NM_001256715.2:c.323-4delG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001256715.2(DNAAF3):​c.323-4delG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,249,968 control chromosomes in the GnomAD database, including 11 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (2 hom.)
• Consequence: DNAAF3 NM_001256715.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.987
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 19-55162293-AC-A is Benign according to our data. Variant chr19-55162293-AC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257687.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00497 (757/152326) while in subpopulation AFR AF = 0.0175 (726/41568). AF 95% confidence interval is 0.0164. There are 9 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256715.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF3	NM_001256715.2	MANE Select	c.323-4delG		splice_region intron	N/A	NP_001243644.1	Q8N9W5-1
	DNAAF3	NM_001256714.1		c.527-4delG		splice_region intron	N/A	NP_001243643.1	Q8N9W5-3
	DNAAF3	NM_178837.4		c.464-4delG		splice_region intron	N/A	NP_849159.2	Q8N9W5-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF3	ENST00000524407.7	TSL:1 MANE Select	c.323-4delG		splice_region intron	N/A	ENSP00000432046.3	Q8N9W5-1
	DNAAF3	ENST00000455045.5	TSL:1	c.161-4delG		splice_region intron	N/A	ENSP00000394343.1	Q8N9W5-7
	DNAAF3	ENST00000528412.5	TSL:1	n.*111-4delG		splice_region intron	N/A	ENSP00000433826.2	Q8N9W5-5

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 757 AN: 152208 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00152 AC: 34 AN: 22308 AF XY: 0.00138

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.000448 AC: 492 AN: 1097642 Hom.: 2 Cov.: 31 AF XY: 0.000453 AC XY: 235 AN XY: 518306

African (AFR) AF: 0.0167 AC: 385 AN: 23024

American (AMR) AF: 0.00127 AC: 11 AN: 8632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14378

East Asian (EAS) AF: 0.00 AC: 0 AN: 26526

South Asian (SAS) AF: 0.00 AC: 0 AN: 19702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36482

Middle Eastern (MID) AF: 0.00164 AC: 7 AN: 4276

European-Non Finnish (NFE) AF: 0.0000402 AC: 37 AN: 920700

Other (OTH) AF: 0.00118 AC: 52 AN: 43922

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152326 Hom.: 9 Cov.: 33 AF XY: 0.00465 AC XY: 346 AN XY: 74488

African (AFR) AF: 0.0175 AC: 726 AN: 41568

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00558

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201986299; hg19: chr19-55673661;