14-49633745-A-T

Position:

• chr14-49633745-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018139.3(DNAAF2):​c.1405T>A​(p.Cys469Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,593,752 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (9 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.995

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043182373).
• BP6: Variant 14-49633745-A-T is Benign according to our data. Variant chr14-49633745-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241280.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr14-49633745-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0021 (320/152270) while in subpopulation NFE AF= 0.00375 (255/68010). AF 95% confidence interval is 0.00337. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.1405T>A	p.Cys469Ser	missense_variant	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.1405T>A	p.Cys469Ser	missense_variant	1/2		NP_001077377.1
DNAAF2	NM_001378453.1	c.-467T>A		5_prime_UTR_variant	1/2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1405T>A	p.Cys469Ser	missense_variant	1/3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.1405T>A	p.Cys469Ser	missense_variant	1/2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00178 AC: 414 AN: 232926 Hom.: 1 AF XY: 0.00162 AC XY: 206 AN XY: 127424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00365

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00469

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.000888

GnomAD4 exome AF: 0.00163 AC: 2347 AN: 1441482 Hom.: 9 Cov.: 92 AF XY: 0.00166 AC XY: 1185 AN XY: 715892

Gnomad4 AFR exome AF: 0.0000910

Gnomad4 AMR exome AF: 0.000211

Gnomad4 ASJ exome AF: 0.00405

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00553

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00272 Hom.: 4

Bravo AF: 0.00147

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00129 AC: 11

ExAC AF: 0.00165 AC: 200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Primary ciliary dyskinesia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

DNAAF2: BP4, BS2 -

DNAAF2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.024
DANN	Benign	0.46
DEOGEN2	Benign	0.00052	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.010
Sift	Benign	0.46	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0	B;B
Vest4		0.047
MutPred		0.30		Gain of catalytic residue at G465 (P = 5e-04);Gain of catalytic residue at G465 (P = 5e-04);
MVP		0.095
MPC		0.63
ClinPred		0.012	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.30

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: rs202079418; hg19: chr14-50100463;