19-55159457-T-C

Variant names:

• chr19-55159457-T-C
• rs28377509
• NM_001256715.2:c.1239-8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256715.2(DNAAF3):​c.1239-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,612,414 control chromosomes in the GnomAD database, including 65,011 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13146 hom., cov: 32)
  • Exomes 𝑓: 0.24 (51865 hom.)
• Consequence: DNAAF3 NM_001256715.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002193
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.43
• Publications: 15 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]

ENSG00000267110 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-55159457-T-C is Benign according to our data. Variant chr19-55159457-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

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.1239-8A>G		splice_region intron	N/A	NP_001243644.1	Q8N9W5-1
	DNAAF3	NM_001256714.1		c.1440-8A>G		splice_region intron	N/A	NP_001243643.1	Q8N9W5-3
	DNAAF3	NM_178837.4		c.1380-8A>G		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.1239-8A>G		splice_region intron	N/A	ENSP00000432046.3	Q8N9W5-1
	DNAAF3	ENST00000455045.5	TSL:1	c.1077-8A>G		splice_region intron	N/A	ENSP00000394343.1	Q8N9W5-7
	DNAAF3	ENST00000528412.5	TSL:1	n.*1027-8A>G		splice_region intron	N/A	ENSP00000433826.2	Q8N9W5-5

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55473 AN: 151980 Hom.: 13106 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.323 AC: 80248 AN: 248766 AF XY: 0.314

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.244 AC: 356674 AN: 1460316 Hom.: 51865 Cov.: 35 AF XY: 0.247 AC XY: 179529 AN XY: 726174

African (AFR) AF: 0.673 AC: 22519 AN: 33440

American (AMR) AF: 0.490 AC: 21901 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5574 AN: 26058

East Asian (EAS) AF: 0.421 AC: 16705 AN: 39648

South Asian (SAS) AF: 0.414 AC: 35687 AN: 86208

European-Finnish (FIN) AF: 0.232 AC: 12367 AN: 53368

Middle Eastern (MID) AF: 0.333 AC: 1922 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223052 AN: 1110806

Other (OTH) AF: 0.281 AC: 16947 AN: 60322

GnomAD4 genome AF: 0.365 AC: 55581 AN: 152098 Hom.: 13146 Cov.: 32 AF XY: 0.367 AC XY: 27290 AN XY: 74352

African (AFR) AF: 0.655 AC: 27178 AN: 41470

American (AMR) AF: 0.405 AC: 6182 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 744 AN: 3468

East Asian (EAS) AF: 0.440 AC: 2272 AN: 5164

South Asian (SAS) AF: 0.440 AC: 2122 AN: 4822

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10586

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13684 AN: 67996

Other (OTH) AF: 0.366 AC: 772 AN: 2110

Alfa AF: 0.271 Hom.: 4789

Bravo AF: 0.391

Asia WGS AF: 0.521 AC: 1808 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.54
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs28377509; hg19: chr19-55670825; COSMIC: COSV61275217; COSMIC: COSV61275217;