rs34777958

Variant names:

• chr16-84176003-C-T
• rs34777958
• NM_178452.6:c.1769C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:11
• Conservation: PhyloP100: -0.892
• Publications: 9 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 -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 Benign/Likely_benign. ClinVar VariationId is 163085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1769C>T	p.Thr590Met	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1061C>T	p.Thr354Met	missense	Exon 7 of 8	NP_001305685.1	Q8NEP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.1769C>T	p.Thr590Met	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1775C>T	p.Thr592Met	missense	Exon 11 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1769C>T	p.Thr590Met	missense	Exon 11 of 13	ENSP00000633753.1

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

GnomAD2 exomes AF: 0.00980 AC: 2465 AN: 251460 AF XY: 0.00978

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 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

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.0104 AC: 463 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86254

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53404

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.0188 AC: 20884 AN: 1111896

Other (OTH) AF: 0.0130 AC: 787 AN: 60390

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

African (AFR) AF: 0.00315 AC: 131 AN: 41568

American (AMR) AF: 0.0132 AC: 202 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1217 AN: 68032

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0149 Hom.: 48

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	3	Primary ciliary dyskinesia 13 (3)
-	-	2	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N
PhyloP100		-0.89
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.0070
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.11	B
Vest4		0.65
MVP		0.067
MPC		0.024
ClinPred		0.0042	T
GERP RS		-1.8
PromoterAI		-0.26	Neutral
Varity_R		0.019
gMVP		0.083
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs34777958; hg19: chr16-84209609; COSMIC: COSV58987848; COSMIC: COSV58987848;