chr8-132572379-G-A

Position:

• chr8-132572379-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012472.6(DNAAF11):​c.1328C>T​(p.Pro443Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08352104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF11	NM_012472.6	c.1328C>T	p.Pro443Leu	missense_variant	12/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5	c.1328C>T	p.Pro443Leu	missense_variant	12/12	1	NM_012472.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1328C>T (p.P443L) alteration is located in exon 12 (coding exon 12) of the LRRC6 gene. This alteration results from a C to T substitution at nucleotide position 1328, causing the proline (P) at amino acid position 443 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.27
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.57	T;T;.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.084	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.085
MutPred		0.16		Loss of glycosylation at P443 (P = 0.0127);Loss of glycosylation at P443 (P = 0.0127);Loss of glycosylation at P443 (P = 0.0127);.;
MVP		0.19
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.075
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-133584627; COSMIC: COSV51543295; COSMIC: COSV51543295;