chr16-84177770-G-A

Variant names:

• chr16-84177770-G-A
• rs4150188
• NM_178452.6:c.2107G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178452.6(DNAAF1):​c.2107G>A​(p.Gly703Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,026 control chromosomes in the GnomAD database, including 64 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G703G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (61 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.900
• Publications: 4 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]

TAF1C (HGNC:11534): (TATA-box binding protein associated factor, RNA polymerase I subunit C) Initiation of transcription by RNA polymerase I requires the formation of a complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs) specific for RNA polymerase I. This complex, known as SL1, binds to the core promoter of ribosomal RNA genes to position the polymerase properly and acts as a channel for regulatory signals. This gene encodes the largest SL1-specific TAF. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2011]

TAF1C Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025303066).
• BP6: Variant 16-84177770-G-A is Benign according to our data. Variant chr16-84177770-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0011 (167/152266) while in subpopulation SAS AF = 0.0311 (150/4828). AF 95% confidence interval is 0.027. There are 3 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	NM_178452.6	MANE Select	c.2107G>A	p.Gly703Arg	missense	Exon 12 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1399G>A	p.Gly467Arg	missense	Exon 8 of 8	NP_001305685.1
	TAF1C	NM_001243156.2	MANE Select	c.*1171C>T		downstream_gene	N/A	NP_001230085.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.2107G>A	p.Gly703Arg	missense	Exon 12 of 12	ENSP00000367815.5
	DNAAF1	ENST00000569735.1	TSL:2	c.502G>A	p.Gly168Arg	missense	Exon 3 of 3	ENSP00000454960.1
	DNAAF1	ENST00000562024.1	TSL:2	n.579G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152148 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00352 AC: 884 AN: 251402 AF XY: 0.00457

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00181 AC: 2640 AN: 1461760 Hom.: 61 Cov.: 31 AF XY: 0.00254 AC XY: 1844 AN XY: 727192

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0272 AC: 2342 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53336

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111974

Other (OTH) AF: 0.00199 AC: 120 AN: 60388

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152266 Hom.: 3 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74452

African (AFR) AF: 0.000120 AC: 5 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000179 Hom.: 1

Bravo AF: 0.000276

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00419 AC: 509

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.9
DANN	Benign	0.97
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.90
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.010
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.050	T
Polyphen		0.039	B
Vest4		0.15
MutPred		0.11		Loss of catalytic residue at V704 (P = 0.0213)
MVP		0.12
MPC		0.17
ClinPred		0.035	T
GERP RS		-5.6
Varity_R		0.076
gMVP		0.075
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs4150188; hg19: chr16-84211376;