rs34777958

chr16-84176003-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178452.6(DNAAF1):c.1769C>T(p.Thr590Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,090 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T590T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 33)
  • Exomes 𝑓: 0.015 (224 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.892

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023761392).
• BP6: Variant 16-84176003-C-T is Benign according to our data. Variant chr16-84176003-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84176003-C-T is described in Lovd as [Likely_benign]. Variant chr16-84176003-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1632/152338) while in subpopulation NFE AF= 0.0179 (1217/68032). AF 95% confidence interval is 0.0171. There are 13 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1769C>T	p.Thr590Met	missense_variant	11/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1769C>T	p.Thr590Met	missense_variant	11/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1632 AN: 152220 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00980 AC: 2465 AN: 251460 Hom.: 22 AF XY: 0.00978 AC XY: 1329 AN XY: 135908

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0154 AC: 22554 AN: 1461752 Hom.: 224 Cov.: 35 AF XY: 0.0151 AC XY: 10972 AN XY: 727178

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0107 AC: 1632 AN: 152338 Hom.: 13 Cov.: 33 AF XY: 0.00920 AC XY: 685 AN XY: 74490

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0148 Hom.: 20

Bravo AF: 0.0118

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.00960 AC: 1166

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr590Met in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 1.6% (138/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs34777958). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 13 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2020

This variant is associated with the following publications: (PMID: 23599692) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0062	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.0070
Sift	Benign	0.13	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.11	B;.
Vest4		0.65
MVP		0.067
MPC		0.024
ClinPred		0.0042	T
GERP RS		-1.8
Varity_R		0.019
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34777958; hg19: chr16-84209609; COSMIC: COSV58987848; COSMIC: COSV58987848;