8-132632921-C-T

Variant names:

• chr8-132632921-C-T
• rs146136398
• NM_012472.6:c.472G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012472.6(DNAAF11):​c.472G>A​(p.Ala158Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A158S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

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.472G>A	p.Ala158Thr	missense	Exon 5 of 12	NP_036604.2
	DNAAF11	NM_001321961.2		c.472G>A	p.Ala158Thr	missense	Exon 5 of 11	NP_001308890.1
	DNAAF11	NM_001321962.2		c.226G>A	p.Ala76Thr	missense	Exon 3 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.472G>A	p.Ala158Thr	missense	Exon 5 of 12	ENSP00000484634.1	Q86X45-1
	DNAAF11	ENST00000519595.5	TSL:1	c.472G>A	p.Ala158Thr	missense	Exon 5 of 12	ENSP00000429791.1	Q86X45-1
	DNAAF11	ENST00000250173.5	TSL:1	c.472G>A	p.Ala158Thr	missense	Exon 5 of 13	ENSP00000250173.2	G5EA20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251184 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727060

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.41		Gain of phosphorylation at A158 (P = 0.0406)
MVP		0.65
MPC		0.40
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.67
Mutation Taster		=37/63	disease causing

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: rs146136398; hg19: chr8-133645167; COSMIC: COSV51540085;