17-3446513-C-T

Variant names:

• chr17-3446513-C-T
• rs770196261
• NM_001170698.2:c.761G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170698.2(SPATA22):​c.761G>A​(p.Arg254His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,609,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R254C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SPATA22 NM_001170698.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847
• Publications: 1 publications found

Genes affected

SPATA22 (HGNC:30705): (spermatogenesis associated 22) Predicted to be involved in regulation of meiotic cell cycle. Predicted to act upstream of or within several processes, including fertilization; gamete generation; and meiosis I cell cycle process. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

SPATA22 Gene-Disease associations (from GenCC):

• genetic infertility

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08979154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170698.2. 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
	SPATA22	NM_001170698.2	MANE Select	c.761G>A	p.Arg254His	missense	Exon 7 of 9	NP_001164169.1	Q8NHS9-1
	SPATA22	NM_001170695.2		c.761G>A	p.Arg254His	missense	Exon 7 of 9	NP_001164166.1	Q8NHS9-1
	SPATA22	NM_001170697.2		c.761G>A	p.Arg254His	missense	Exon 7 of 9	NP_001164168.1	Q8NHS9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATA22	ENST00000572969.6	TSL:1 MANE Select	c.761G>A	p.Arg254His	missense	Exon 7 of 9	ENSP00000460187.1	Q8NHS9-1
	SPATA22	ENST00000397168.7	TSL:1	c.761G>A	p.Arg254His	missense	Exon 7 of 9	ENSP00000380354.3	Q8NHS9-1
	SPATA22	ENST00000573128.5	TSL:1	c.761G>A	p.Arg254His	missense	Exon 7 of 9	ENSP00000459580.1	Q8NHS9-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246504 AF XY: 0.0000376

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1456882 Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7 AN XY: 724440

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000904 AC: 3 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 43906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1110128

Other (OTH) AF: 0.00 AC: 0 AN: 60186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000511455), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.85
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.072
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.017	B
Vest4		0.082
MutPred		0.26		Loss of MoRF binding (P = 0.0251)
MVP		0.55
MPC		0.030
ClinPred		0.052	T
GERP RS		-0.49
Varity_R		0.038
gMVP		0.37
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs770196261; hg19: chr17-3349807;