rs2288020

Variant names:

• chr16-84176132-T-C
• rs2288020
• NM_178452.6:c.1898T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-84176132-T-C
• chr16-84176132-T-A

Variant summary

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

The NM_178452.6(DNAAF1):​c.1898T>C​(p.Leu633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,394 control chromosomes in the GnomAD database, including 100,022 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L633F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7327 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92695 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.12
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.13282E-4).
• BP6: Variant 16-84176132-T-C is Benign according to our data. Variant chr16-84176132-T-C is described in ClinVar as Benign. ClinVar VariationId is 163087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 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.1898T>C	p.Leu633Ser	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1190T>C	p.Leu397Ser	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.1898T>C	p.Leu633Ser	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1904T>C	p.Leu635Ser	missense	Exon 11 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1898T>C	p.Leu633Ser	missense	Exon 11 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43702 AN: 151810 Hom.: 7313 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.345 AC: 86355 AN: 250160 AF XY: 0.343

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.352 AC: 514435 AN: 1461466 Hom.: 92695 Cov.: 59 AF XY: 0.349 AC XY: 253665 AN XY: 727002

African (AFR) AF: 0.0967 AC: 3237 AN: 33474

American (AMR) AF: 0.464 AC: 20700 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7765 AN: 26132

East Asian (EAS) AF: 0.377 AC: 14947 AN: 39692

South Asian (SAS) AF: 0.269 AC: 23197 AN: 86258

European-Finnish (FIN) AF: 0.362 AC: 19325 AN: 53370

Middle Eastern (MID) AF: 0.273 AC: 1574 AN: 5768

European-Non Finnish (NFE) AF: 0.363 AC: 403784 AN: 1111750

Other (OTH) AF: 0.330 AC: 19906 AN: 60378

GnomAD4 genome AF: 0.288 AC: 43724 AN: 151928 Hom.: 7327 Cov.: 32 AF XY: 0.292 AC XY: 21664 AN XY: 74244

African (AFR) AF: 0.108 AC: 4488 AN: 41426

American (AMR) AF: 0.390 AC: 5951 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1052 AN: 3466

East Asian (EAS) AF: 0.371 AC: 1904 AN: 5136

South Asian (SAS) AF: 0.272 AC: 1309 AN: 4816

European-Finnish (FIN) AF: 0.367 AC: 3873 AN: 10560

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24054 AN: 67952

Other (OTH) AF: 0.290 AC: 611 AN: 2104

Alfa AF: 0.329 Hom.: 29809

Bravo AF: 0.287

TwinsUK AF: 0.376 AC: 1394

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.111 AC: 489

ESP6500EA AF: 0.355 AC: 3054

ExAC AF: 0.336 AC: 40791

Asia WGS AF: 0.282 AC: 981 AN: 3478

EpiCase AF: 0.343

EpiControl AF: 0.348

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)
-	-	1	Primary ciliary dyskinesia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.010
DANN	Benign	0.37
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.00031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.85	L
PhyloP100		-3.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.030
Sift	Benign	0.74	T
Sift4G	Benign	0.83	T
Polyphen		0.10	B
Vest4		0.034
MPC		0.022
ClinPred		0.0045	T
GERP RS		-3.4
PromoterAI		0.023	Neutral
Varity_R		0.023
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2288020; hg19: chr16-84209738; COSMIC: COSV58984738; COSMIC: COSV58984738;