rs74349463

Variant names:

• chr17-44901658-T-C
• rs74349463
• NM_213607.3:c.276+6T>C

Variant summary

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

The NM_213607.3(DNAAF19):​c.276+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,454 control chromosomes in the GnomAD database, including 19,755 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 0.13 (1376 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18379 hom.)
• Consequence: DNAAF19 NM_213607.3 splice_region, intron
• Scores: Splicing: ADA: 0.08650
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.298
• Publications: 12 publications found

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF19 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 17

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-44901658-T-C is Benign according to our data. Variant chr17-44901658-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 263318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF19	NM_213607.3	c.276+6T>C		splice_region_variant, intron_variant	Intron 3 of 3	ENST00000417826.3	NP_998772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC103	ENST00000417826.3	c.276+6T>C		splice_region_variant, intron_variant	Intron 3 of 3	1	NM_213607.3	ENSP00000391692.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19130 AN: 152086 Hom.: 1378 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.134 AC: 33561 AN: 250970 AF XY: 0.140

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.00734

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.155 AC: 226189 AN: 1461250 Hom.: 18379 Cov.: 32 AF XY: 0.156 AC XY: 113169 AN XY: 726926

African (AFR) AF: 0.0623 AC: 2086 AN: 33472

American (AMR) AF: 0.0755 AC: 3376 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4735 AN: 26106

East Asian (EAS) AF: 0.00529 AC: 210 AN: 39698

South Asian (SAS) AF: 0.163 AC: 14010 AN: 86210

European-Finnish (FIN) AF: 0.154 AC: 8200 AN: 53416

Middle Eastern (MID) AF: 0.199 AC: 1139 AN: 5710

European-Non Finnish (NFE) AF: 0.165 AC: 183629 AN: 1111586

Other (OTH) AF: 0.146 AC: 8804 AN: 60354

GnomAD4 genome AF: 0.126 AC: 19125 AN: 152204 Hom.: 1376 Cov.: 32 AF XY: 0.123 AC XY: 9187 AN XY: 74398

African (AFR) AF: 0.0639 AC: 2656 AN: 41558

American (AMR) AF: 0.0930 AC: 1422 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3468

East Asian (EAS) AF: 0.00869 AC: 45 AN: 5180

South Asian (SAS) AF: 0.159 AC: 770 AN: 4830

European-Finnish (FIN) AF: 0.150 AC: 1583 AN: 10586

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11507 AN: 67982

Other (OTH) AF: 0.128 AC: 271 AN: 2112

Alfa AF: 0.138 Hom.: 905

Bravo AF: 0.117

Asia WGS AF: 0.0830 AC: 288 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary ciliary dyskinesia 17 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.086
dbscSNV1_RF	Benign	0.18
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: rs74349463; hg19: chr17-42979026;