19-55159274-C-T

Position:

• chr19-55159274-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001256715.2(DNAAF3):​c.1414G>A​(p.Gly472Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.88

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ENSG00000267110 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0143066645).
• BP6: Variant 19-55159274-C-T is Benign according to our data. Variant chr19-55159274-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr19-55159274-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000302 (46/152308) while in subpopulation AMR AF= 0.000849 (13/15306). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.1414G>A	p.Gly472Arg	missense_variant	12/12	ENST00000524407.7	NP_001243644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.1414G>A	p.Gly472Arg	missense_variant	12/12	1	NM_001256715.2	ENSP00000432046.3
ENSG00000267110	ENST00000587871.1	n.397G>A		non_coding_transcript_exon_variant	4/9	5		ENSP00000473050.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000357 AC: 89 AN: 249208 Hom.: 0 AF XY: 0.000377 AC XY: 51 AN XY: 135252

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.000254 AC XY: 185 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74486

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000372 AC: 45

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 539 of the DNAAF3 protein (p.Gly539Arg). This variant is present in population databases (rs201919395, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 330208). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2022	This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.2
DANN	Benign	0.52
DEOGEN2	Benign	0.0023	.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.50	T;T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.060	N;.;.;N
REVEL	Benign	0.068
Sift	Benign	0.23	T;.;.;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0070	.;B;.;.
Vest4		0.066
MutPred		0.32		.;Gain of loop (P = 0.0321);.;.;
MVP		0.030
MPC		0.28
ClinPred		0.010	T
GERP RS		-7.0
Varity_R		0.047
gMVP		0.35

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: rs201919395; hg19: chr19-55670642;