chr7-770582-T-C

Variant names:

• chr7-770582-T-C
• rs4720951
• NM_017802.4:c.1895T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017802.4(DNAAF5):​c.1895T>C​(p.Val632Ala) variant causes a missense change. The variant allele was found at a frequency of 0.454 in 1,613,284 control chromosomes in the GnomAD database, including 168,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14620 hom., cov: 34)
  • Exomes 𝑓: 0.46 (153791 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.94
• Publications: 40 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: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.004177332).
• BP6: Variant 7-770582-T-C is Benign according to our data. Variant chr7-770582-T-C is described in ClinVar as Benign. ClinVar VariationId is 260930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	NM_017802.4	MANE Select	c.1895T>C	p.Val632Ala	missense	Exon 9 of 13	NP_060272.3
	DNAAF5	NR_075098.2		n.1855T>C		non_coding_transcript_exon	Exon 9 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.1895T>C	p.Val632Ala	missense	Exon 9 of 13	ENSP00000297440.6
	DNAAF5	ENST00000403952.3	TSL:1	c.170T>C	p.Val57Ala	missense	Exon 2 of 6	ENSP00000384884.3
	DNAAF5	ENST00000440747.5	TSL:2	c.1298T>C	p.Val433Ala	missense	Exon 9 of 13	ENSP00000403165.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65803 AN: 152002 Hom.: 14599 Cov.: 34

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.434 AC: 108814 AN: 250670 AF XY: 0.434

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.457 AC: 667023 AN: 1461164 Hom.: 153791 Cov.: 49 AF XY: 0.455 AC XY: 330459 AN XY: 726926

African (AFR) AF: 0.355 AC: 11872 AN: 33480

American (AMR) AF: 0.408 AC: 18239 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 12102 AN: 26122

East Asian (EAS) AF: 0.320 AC: 12708 AN: 39692

South Asian (SAS) AF: 0.365 AC: 31446 AN: 86244

European-Finnish (FIN) AF: 0.513 AC: 27194 AN: 53038

Middle Eastern (MID) AF: 0.475 AC: 2740 AN: 5768

European-Non Finnish (NFE) AF: 0.471 AC: 523494 AN: 1111736

Other (OTH) AF: 0.451 AC: 27228 AN: 60376

GnomAD4 genome AF: 0.433 AC: 65858 AN: 152120 Hom.: 14620 Cov.: 34 AF XY: 0.432 AC XY: 32165 AN XY: 74390

African (AFR) AF: 0.358 AC: 14848 AN: 41516

American (AMR) AF: 0.459 AC: 7017 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1571 AN: 3466

East Asian (EAS) AF: 0.337 AC: 1738 AN: 5164

South Asian (SAS) AF: 0.366 AC: 1768 AN: 4830

European-Finnish (FIN) AF: 0.515 AC: 5449 AN: 10582

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31898 AN: 67954

Other (OTH) AF: 0.459 AC: 965 AN: 2104

Alfa AF: 0.454 Hom.: 34299

Bravo AF: 0.427

TwinsUK AF: 0.454 AC: 1685

ALSPAC AF: 0.482 AC: 1859

ESP6500AA AF: 0.356 AC: 1569

ESP6500EA AF: 0.471 AC: 4049

ExAC AF: 0.429 AC: 52105

Asia WGS AF: 0.414 AC: 1440 AN: 3478

EpiCase AF: 0.482

EpiControl AF: 0.484

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.97	T
PhyloP100		3.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Uncertain	0.013	D
Polyphen		0.014	B
Vest4		0.12
MPC		0.20
ClinPred		0.016	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.28
Mutation Taster		=79/21	polymorphism (auto)

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: rs4720951; hg19: chr7-810219; COSMIC: COSV52413848;