NM_213607.3:c.276+6T>C

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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF19	NM_213607.3	MANE Select	c.276+6T>C		splice_region intron	N/A	NP_998772.1
	DNAAF19	NM_001258395.2		c.276+6T>C		splice_region intron	N/A	NP_001245324.1
	DNAAF19	NM_001258396.2		c.276+6T>C		splice_region intron	N/A	NP_001245325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC103	ENST00000417826.3	TSL:1 MANE Select	c.276+6T>C		splice_region intron	N/A	ENSP00000391692.2
	CCDC103	ENST00000410006.6	TSL:2	c.276+6T>C		splice_region intron	N/A	ENSP00000387252.1
	CCDC103	ENST00000357776.6	TSL:2	c.276+6T>C		splice_region intron	N/A	ENSP00000350420.2

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	Primary ciliary dyskinesia 17 (1)

Computational scores

Source: dbNSFP v4.9

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;