1-117963816-T-G

Variant names:

• chr1-117963816-T-G
• NM_206996.4:c.6655A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_206996.4(SPAG17):​c.6655A>C​(p.Lys2219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPAG17 NM_206996.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.211

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]

WDR3 (HGNC:12755): (WD repeat domain 3) This gene encodes a nuclear protein containing 10 WD repeats. WD repeats are approximately 30- to 40-amino acid domains containing several conserved residues, which usually include a trp-asp at the C-terminal end. Proteins belonging to the WD repeat family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054211617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG17	NM_206996.4	c.6655A>C	p.Lys2219Gln	missense_variant	Exon 48 of 49	ENST00000336338.10	NP_996879.1
WDR3	NM_006784.3	c.*4369T>G		3_prime_UTR_variant	Exon 27 of 27	ENST00000349139.6	NP_006775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAG17	ENST00000336338.10	c.6655A>C	p.Lys2219Gln	missense_variant	Exon 48 of 49	1	NM_206996.4	ENSP00000337804.5
WDR3	ENST00000349139.6	c.*4369T>G		3_prime_UTR_variant	Exon 27 of 27	1	NM_006784.3	ENSP00000308179.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6655A>C (p.K2219Q) alteration is located in exon 48 (coding exon 48) of the SPAG17 gene. This alteration results from a A to C substitution at nucleotide position 6655, causing the lysine (K) at amino acid position 2219 to be replaced by a glutamine (Q). 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	0.099
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.4
DANN	Benign	0.63
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.0090
Sift	Benign	0.12	T
Sift4G	Uncertain	0.034	D
Polyphen		0.021	B
Vest4		0.11
MutPred		0.23		Loss of methylation at K2219 (P = 0.006);
MVP		0.061
MPC		0.051
ClinPred		0.029	T
GERP RS		-0.44
Varity_R		0.065
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr1-118506439;