rs61743547

Variant names:

• chr16-84149110-C-T
• rs61743547
• NM_178452.6:c.228C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_178452.6(DNAAF1):​c.228C>T​(p.His76His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,614,006 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (56 hom., cov: 29)
  • Exomes 𝑓: 0.019 (425 hom.)
• Consequence: DNAAF1 NM_178452.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.106
• Publications: 4 publications found

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 13

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-84149110-C-T is Benign according to our data. Variant chr16-84149110-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.106 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2705/152184) while in subpopulation NFE AF = 0.0179 (1218/68022). AF 95% confidence interval is 0.0171. There are 56 homozygotes in GnomAd4. There are 1509 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. 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
	DNAAF1	NM_178452.6	MANE Select	c.228C>T	p.His76His	synonymous	Exon 2 of 12	NP_848547.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.228C>T	p.His76His	synonymous	Exon 2 of 12	ENSP00000367815.5
	DNAAF1	ENST00000567918.5	TSL:1	n.228C>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000455154.1
	DNAAF1	ENST00000963697.1		c.228C>T	p.His76His	synonymous	Exon 2 of 13	ENSP00000633756.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2706 AN: 152066 Hom.: 56 Cov.: 29

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0194 AC: 4883 AN: 251486 AF XY: 0.0193

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.0539

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0874

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0185 AC: 27069 AN: 1461822 Hom.: 425 Cov.: 32 AF XY: 0.0181 AC XY: 13188 AN XY: 727224

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.00669 AC: 299 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0532 AC: 1390 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00590 AC: 509 AN: 86258

European-Finnish (FIN) AF: 0.0805 AC: 4302 AN: 53416

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.0173 AC: 19199 AN: 1111950

Other (OTH) AF: 0.0203 AC: 1223 AN: 60392

GnomAD4 genome AF: 0.0178 AC: 2705 AN: 152184 Hom.: 56 Cov.: 29 AF XY: 0.0203 AC XY: 1509 AN XY: 74382

African (AFR) AF: 0.00313 AC: 130 AN: 41522

American (AMR) AF: 0.0113 AC: 172 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.0868 AC: 919 AN: 10586

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1218 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0186 Hom.: 19

Bravo AF: 0.0119

Asia WGS AF: 0.00346 AC: 12 AN: 3478

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 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.61
DANN	Benign	0.75
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61743547; hg19: chr16-84182715;