rs377278570

Positions:

• chr8-132675492-A-G
• chr8-132675492-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_012472.6(DNAAF11):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,356 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAAF11 NM_012472.6 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.35

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF11	NM_012472.6	c.2T>C	p.Met1?	start_lost	1/12	ENST00000620350.5	NP_036604.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF11	ENST00000620350.5	c.2T>C	p.Met1?	start_lost	1/12	1	NM_012472.6	ENSP00000484634	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416356 Hom.: 0 Cov.: 30 AF XY: 0.00000284 AC XY: 2 AN XY: 703728

Gnomad4 AFR exome AF: 0.0000321

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-3.0	.;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;D;.;.
Vest4		0.87
MutPred		0.99		Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);
MVP		0.37
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.78
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs377278570; hg19: chr8-133687738;