rs149631064

Variant names:

• chr8-132572462-T-C
• rs149631064
• NM_012472.6:c.1245A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_012472.6(DNAAF11):​c.1245A>G​(p.Lys415Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,602,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (8 hom.)
• Consequence: DNAAF11 NM_012472.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.625
• Publications: 0 publications found

Genes affected

DNAAF11 (HGNC:16725): (dynein axonemal assembly factor 11) The protein encoded by this gene contains several leucine-rich repeat domains and appears to be involved in the motility of cilia. Defects in this gene are a cause of primary ciliary dyskinesia-19 (CILD19). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 4, 11 and 22. [provided by RefSeq, Apr 2016]

DNAAF11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 19

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-132572462-T-C is Benign according to our data. Variant chr8-132572462-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260271.
• BP7: Synonymous conserved (PhyloP=0.625 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012472.6. 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
	DNAAF11	NM_012472.6	MANE Select	c.1245A>G	p.Lys415Lys	synonymous	Exon 12 of 12	NP_036604.2
	DNAAF11	NM_001321961.2		c.1185A>G	p.Lys395Lys	synonymous	Exon 11 of 11	NP_001308890.1
	DNAAF11	NM_001321962.2		c.999A>G	p.Lys333Lys	synonymous	Exon 10 of 10	NP_001308891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF11	ENST00000620350.5	TSL:1 MANE Select	c.1245A>G	p.Lys415Lys	synonymous	Exon 12 of 12	ENSP00000484634.1	Q86X45-1
	DNAAF11	ENST00000519595.5	TSL:1	c.1245A>G	p.Lys415Lys	synonymous	Exon 12 of 12	ENSP00000429791.1	Q86X45-1
	DNAAF11	ENST00000250173.5	TSL:1	c.*109A>G		3_prime_UTR	Exon 13 of 13	ENSP00000250173.2	G5EA20

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00125 AC: 301 AN: 240316 AF XY: 0.00124

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000917

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.000590 AC: 855 AN: 1449998 Hom.: 8 Cov.: 30 AF XY: 0.000648 AC XY: 467 AN XY: 721078

African (AFR) AF: 0.0000608 AC: 2 AN: 32868

American (AMR) AF: 0.00103 AC: 44 AN: 42690

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 580 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.00 AC: 0 AN: 83644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1107102

Other (OTH) AF: 0.00182 AC: 109 AN: 59884

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000524 AC: 8 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00176 Hom.: 1

Bravo AF: 0.000714

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia 19 (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

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: rs149631064; hg19: chr8-133584710;