rs183758503

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_206996.4(SPAG17):c.1069G>C(p.Asp357His) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SPAG17
NM_206996.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.09

Variant links:

Genes affected

SPAG17 (HGNC:26620): (sperm associated antigen 17) This gene encodes a central pair protein present in the axonemes of cells with a "9 + 2" organization of microtubules. The encoded protein is required for the proper function of the axoneme. Mutations in the orthologous gene in mice lead to primary ciliary dyskinesia characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress, hydrocephalus, and neonatal lethality within twelve hours of birth due to impaired airway mucociliary clearance. Single-nucleotide polymorphisms in this gene are associated with human height and targeted mutations lead to skeletal malformations affecting the limbs in mice, suggesting a role for this gene in skeletal development. [provided by RefSeq, Feb 2017]

SPAG17 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-118093260-C-G is Pathogenic according to our data. Variant chr1-118093260-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437866.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3409052).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG17	NM_206996.4 linkuse as main transcript	c.1069G>C	p.Asp357His	missense_variant	8/49	ENST00000336338.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG17	ENST00000336338.10 linkuse as main transcript	c.1069G>C	p.Asp357His	missense_variant	8/49	1	NM_206996.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000196

AC:

AN:

250134

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000376

AC:

AN:

1461294

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00123

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cranioectodermal dysplasia 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratorio de Citogenómica y Microarreglos, Universidad Autonoma de Nuevo Leon

Aug 27, 2017

SPAG17 is essential for function and structure of motile cilia since it is part of the axonemal structure. It has been suggested to present a role in skeletal and bone development. Next generation sequencing We focused on homozygous variants with a population frequency <0.01% and predicted to be pathogenic, likely pathogenic or variant of uncertain significance (VUS) by the SIFT, PANTHER, Mutation Taster 2, PhD-SNP, PROVEAN, and PolyPhen-2 platforms. Sequence conservation was evaluated by PhyloP, PhastCons and GERP scores; while MuPro and CFSSP from ExPASy were used to predict changes in the protein secondary structure. Results: The sequence analysis showed the homozygous missense variant c.1069G>C in SPAG17 resulting in the amino acid exchange p.Asp357His; the total read depth for this variant was 32x (GQX=84). This variant has not yet been reported in NHLBI Exome Sequencing Project (ESP) or ClinVar databases; but the Exome Aggregation Consortium (ExAC) browser reported this variant but as heterozygous in 22 Latinos (22/114272), with a population frequency of 0.0001925 (http://exac.broadinstitute.org/variant/1-118635883-C-G). According to conservation scores (PhastCons = 0.998, Phylop = 3.68, and GERP = 4.73), this position is highly conserved. Thus, PROVEAN, SIFT, PolyPhen-2, PANTHER, Mutation taster 2 and PhD-SNP software predicted this variation to be deleterious or probably damaging. In addition, CFSSP tool and MuPro web app predicted both loss of a little Î±-helix and instability for the mutated protein, respectively. Therefore, Asp357 is an evolutionary conserved amino acid and seem to play an important role in the respective protein structure. This is consistent with interpretation of the variant by ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Uncertain

0.13

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

M_CAP

Benign

0.066

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.78

MPC

0.35

ClinPred

0.81

GERP RS

4.7

Varity_R

0.41

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over