2-227893904-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_178821.3(DAW1):c.427A>G(p.Asn143Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DAW1 NM_178821.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.45

Genes affected

DAW1 (HGNC:26383): (dynein assembly factor with WD repeats 1) Predicted to act upstream of or within several processes, including cerebrospinal fluid circulation; determination of left/right symmetry; and outer dynein arm assembly. Predicted to be located in cilium and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 2-227893904-A-G is Pathogenic according to our data. Variant chr2-227893904-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1325631.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAW1	NM_178821.3	c.427A>G	p.Asn143Asp	missense_variant	5/13	ENST00000309931.3
DAW1	NM_001330004.2	c.382A>G	p.Asn128Asp	missense_variant	6/14
DAW1	XM_047443536.1	c.382A>G	p.Asn128Asp	missense_variant	7/15
DAW1	NR_138459.2	n.486A>G		non_coding_transcript_exon_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAW1	ENST00000309931.3	c.427A>G	p.Asn143Asp	missense_variant	5/13	1	NM_178821.3	P1
DAW1	ENST00000472604.1	n.375A>G		non_coding_transcript_exon_variant	4/5	2
DAW1	ENST00000373666.6	c.427A>G	p.Asn143Asp	missense_variant, NMD_transcript_variant	5/14	2
DAW1	ENST00000454999.5	c.*368A>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, no assertion criteria provided

research

New Leaf Center

-

- -

Ciliary dyskinesia, primary, 52 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.41
Sift	Benign	0.035	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.89
MVP		0.70
MPC		0.51
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.88
gMVP		0.42

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: rs1265774517; hg19: chr2-228758620;