rs61743547

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6	c.228C>T	p.His76His	synonymous_variant	Exon 2 of 12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.228C>T	p.His76His	synonymous_variant	Exon 2 of 12	1	NM_178452.6	ENSP00000367815.5
DNAAF1	ENST00000567918.5	n.228C>T		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000455154.1
DNAAF1	ENST00000563093.5	n.228C>T		non_coding_transcript_exon_variant	Exon 2 of 11	2		ENSP00000457373.1
DNAAF1	ENST00000570298.5	n.382C>T		non_coding_transcript_exon_variant	Exon 2 of 11	2

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

GnomAD3 exomes AF: 0.0194 AC: 4883 AN: 251486 Hom.: 128 AF XY: 0.0193 AC XY: 2630 AN XY: 135918

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 SAS exome AF: 0.00578

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

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.0532

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00590

Gnomad4 FIN exome AF: 0.0805

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0203

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

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0868

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0186 Hom.: 19

Bravo AF: 0.0119

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His76His in exon 2 of DNAAF1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.0% (176/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs61743547). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Jan 16, 2019

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 13 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.61
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs61743547; hg19: chr16-84182715;