8-132572449-G-T

Variant names:

• chr8-132572449-G-T
• rs1554667007
• NM_012472.6:c.1258C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012472.6(DNAAF11):​c.1258C>A​(p.Pro420Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39459044).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF11	NM_012472.6	MANE Select	c.1258C>A	p.Pro420Thr	missense	Exon 12 of 12	NP_036604.2
	DNAAF11	NM_001321961.2		c.1198C>A	p.Pro400Thr	missense	Exon 11 of 11	NP_001308890.1
	DNAAF11	NM_001321962.2		c.1012C>A	p.Pro338Thr	missense	Exon 10 of 10	NP_001308891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF11	ENST00000620350.5	TSL:1 MANE Select	c.1258C>A	p.Pro420Thr	missense	Exon 12 of 12	ENSP00000484634.1
	DNAAF11	ENST00000519595.5	TSL:1	c.1258C>A	p.Pro420Thr	missense	Exon 12 of 12	ENSP00000429791.1
	DNAAF11	ENST00000250173.5	TSL:1	c.*122C>A		3_prime_UTR	Exon 13 of 13	ENSP00000250173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723000

African (AFR) AF: 0.00 AC: 0 AN: 33088

American (AMR) AF: 0.00 AC: 0 AN: 43760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 84640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107948

Other (OTH) AF: 0.00 AC: 0 AN: 60000

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 19 Uncertain:1

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with threonine at codon 420 of the LRRC6 protein (p.Pro420Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an LRRC6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.24		Loss of helix (P = 0.0376)
MVP		0.55
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.41
gMVP		0.43
Mutation Taster		=90/10	polymorphism

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: rs1554667007; hg19: chr8-133584697;