1-117963818-C-T

Variant names:

• chr1-117963818-C-T
• rs112012491
• NM_206996.4:c.6653G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_206996.4(SPAG17):​c.6653G>A​(p.Arg2218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,268 control chromosomes in the GnomAD database, including 33 homozygotes. 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 Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2218C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (33 hom.)
• Consequence: SPAG17 NM_206996.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.448
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034430623).
• BP6: Variant 1-117963818-C-T is Benign according to our data. Variant chr1-117963818-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3038251.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 33 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206996.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG17	NM_206996.4	MANE Select	c.6653G>A	p.Arg2218His	missense	Exon 48 of 49	NP_996879.1	Q6Q759
	WDR3	NM_006784.3	MANE Select	c.*4371C>T		3_prime_UTR	Exon 27 of 27	NP_006775.1	Q9UNX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG17	ENST00000336338.10	TSL:1 MANE Select	c.6653G>A	p.Arg2218His	missense	Exon 48 of 49	ENSP00000337804.5	Q6Q759
	WDR3	ENST00000349139.6	TSL:1 MANE Select	c.*4371C>T		3_prime_UTR	Exon 27 of 27	ENSP00000308179.4	Q9UNX4
	SPAG17	ENST00000466857.5	TSL:3	n.235G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152072 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00396 AC: 991 AN: 250058 AF XY: 0.00458

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00334 AC: 4877 AN: 1460078 Hom.: 33 Cov.: 30 AF XY: 0.00367 AC XY: 2667 AN XY: 726322

African (AFR) AF: 0.00344 AC: 115 AN: 33424

American (AMR) AF: 0.00187 AC: 83 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00357 AC: 93 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0154 AC: 1321 AN: 86000

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53368

Middle Eastern (MID) AF: 0.00782 AC: 45 AN: 5756

European-Non Finnish (NFE) AF: 0.00268 AC: 2976 AN: 1111080

Other (OTH) AF: 0.00377 AC: 227 AN: 60282

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.00313 AC XY: 233 AN XY: 74402

African (AFR) AF: 0.00361 AC: 150 AN: 41522

American (AMR) AF: 0.00334 AC: 51 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4828

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00293 Hom.: 2

Bravo AF: 0.00312

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00430 AC: 522

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00351

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SPAG17-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.86	L
PhyloP100		-0.45
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.012
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.012	B
Vest4		0.096
MVP		0.048
MPC		0.058
ClinPred		0.0040	T
GERP RS		-0.82
Varity_R		0.041
gMVP		0.36
Mutation Taster		=99/1	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: rs112012491; hg19: chr1-118506441; COSMIC: COSV105202141; COSMIC: COSV105202141;