7-774112-G-A

Variant names:

• chr7-774112-G-A
• rs750935190
• NM_017802.4:c.1996G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_017802.4(DNAAF5):​c.1996G>A​(p.Ala666Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000143 in 1,613,412 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A666V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.93
• Publications: 0 publications found

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

DNAAF5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. 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
	DNAAF5	NM_017802.4	MANE Select	c.1996G>A	p.Ala666Thr	missense	Exon 10 of 13	NP_060272.3
	DNAAF5	NR_075098.2		n.1956G>A		non_coding_transcript_exon	Exon 10 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.1996G>A	p.Ala666Thr	missense	Exon 10 of 13	ENSP00000297440.6	Q86Y56-1
	DNAAF5	ENST00000403952.3	TSL:1	c.271G>A	p.Ala91Thr	missense	Exon 3 of 6	ENSP00000384884.3	E9PGY2
	DNAAF5	ENST00000852634.1		c.2077G>A	p.Ala693Thr	missense	Exon 11 of 14	ENSP00000522693.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000640 AC: 16 AN: 249972 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461200 Hom.: 1 Cov.: 38 AF XY: 0.000142 AC XY: 103 AN XY: 726938

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 204 AN: 1111970

Other (OTH) AF: 0.000166 AC: 10 AN: 60388

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.0040	T
PhyloP100		6.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.24
MPC		0.67
ClinPred		0.75	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.45
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs750935190; hg19: chr7-813749;