NM_178452.6:c.1975C>G

Variant names:

• chr16-84176209-C-G
• rs2288021
• NM_178452.6:c.1975C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_178452.6(DNAAF1):​c.1975C>G​(p.Leu659Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,716 control chromosomes in the GnomAD database, including 34,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L659P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2577 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32338 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.430
• Publications: 18 publications found

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 13

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-84176209-C-G is Benign according to our data. Variant chr16-84176209-C-G is described in ClinVar as Benign. ClinVar VariationId is 163088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. 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
	DNAAF1	NM_178452.6	MANE Select	c.1975C>G	p.Leu659Val	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1267C>G	p.Leu423Val	missense	Exon 7 of 8	NP_001305685.1	Q8NEP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.1975C>G	p.Leu659Val	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1981C>G	p.Leu661Val	missense	Exon 11 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1975C>G	p.Leu659Val	missense	Exon 11 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24898 AN: 152118 Hom.: 2576 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.199 AC: 50022 AN: 250950 AF XY: 0.202

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.207 AC: 302398 AN: 1461480 Hom.: 32338 Cov.: 70 AF XY: 0.208 AC XY: 150975 AN XY: 727048

African (AFR) AF: 0.0357 AC: 1194 AN: 33480

American (AMR) AF: 0.217 AC: 9719 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5743 AN: 26136

East Asian (EAS) AF: 0.0975 AC: 3870 AN: 39700

South Asian (SAS) AF: 0.214 AC: 18422 AN: 86256

European-Finnish (FIN) AF: 0.211 AC: 11212 AN: 53078

Middle Eastern (MID) AF: 0.279 AC: 1609 AN: 5768

European-Non Finnish (NFE) AF: 0.214 AC: 238319 AN: 1111974

Other (OTH) AF: 0.204 AC: 12310 AN: 60388

GnomAD4 genome AF: 0.164 AC: 24891 AN: 152236 Hom.: 2577 Cov.: 33 AF XY: 0.162 AC XY: 12030 AN XY: 74422

African (AFR) AF: 0.0411 AC: 1707 AN: 41562

American (AMR) AF: 0.203 AC: 3096 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3470

East Asian (EAS) AF: 0.111 AC: 576 AN: 5170

South Asian (SAS) AF: 0.208 AC: 1006 AN: 4830

European-Finnish (FIN) AF: 0.202 AC: 2147 AN: 10606

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14958 AN: 67992

Other (OTH) AF: 0.186 AC: 394 AN: 2116

Alfa AF: 0.208 Hom.: 1129

Bravo AF: 0.159

TwinsUK AF: 0.207 AC: 768

ALSPAC AF: 0.201 AC: 775

ESP6500AA AF: 0.0436 AC: 192

ESP6500EA AF: 0.218 AC: 1878

ExAC AF: 0.197 AC: 23939

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.221

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 13 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.1
DANN	Benign	0.89
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.43
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.032
Sift	Uncertain	0.022	D
Sift4G	Benign	0.093	T
Polyphen		0.013	B
Vest4		0.020
MPC		0.020
ClinPred		0.0023	T
GERP RS		0.29
PromoterAI		0.039	Neutral
Varity_R		0.049
gMVP		0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2288021; hg19: chr16-84209815; COSMIC: COSV58987654; COSMIC: COSV58987654;