rs199904329

Variant names:

• chrX-141241547-C-T
• rs199904329
• NM_022661.4:c.264G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_022661.4(SPANXC):​c.264G>A​(p.Met88Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 5 hem., cov: 9)
  • Exomes 𝑓: 0.00025 (2 hom. 58 hem.)
  • Failed GnomAD Quality Control
• Consequence: SPANXC NM_022661.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.602
• Publications: 2 publications found

Genes affected

SPANXC (HGNC:14331): (SPANX family member C) Temporally regulated transcription and translation of several testis-specific genes is required to initiate the series of molecular and morphological changes in the male germ cell lineage necessary for the formation of mature spermatozoa. This gene is a member of the SPANX family, which is located in a gene cluster on chromosome X. The SPANX genes encode differentially expressed testis-specific proteins that localize to various subcellular compartments. This particular gene encodes a protein that localizes to the nucleus and is expressed in highly metastatic cell lines, making the protein a potential diagnostic and prognostic marker. The protein belongs to a family of cancer/testis antigens and represents a potential target for cancer immunotherapy. [provided by RefSeq, Jul 2008]

SPANXA2-OT1 (HGNC:31683): (SPANXA2 overlapping transcript 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02366817).
• BP6: Variant X-141241547-C-T is Benign according to our data. Variant chrX-141241547-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2661546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022661.4. 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
	SPANXC	NM_022661.4	MANE Select	c.264G>A	p.Met88Ile	missense	Exon 2 of 2	NP_073152.2	Q9NY87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPANXC	ENST00000358993.3	TSL:1 MANE Select	c.264G>A	p.Met88Ile	missense	Exon 2 of 2	ENSP00000351884.2	Q9NY87
	SPANXA2-OT1	ENST00000662492.1		n.102+53710C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000280 AC: 18 AN: 64340 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00463

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000101

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000136 AC: 22 AN: 161982 AF XY: 0.0000371

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000827

Gnomad FIN exome AF: 0.0000666

Gnomad NFE exome AF: 0.0000951

Gnomad OTH exome AF: 0.000249

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000246 AC: 246 AN: 1001296 Hom.: 2 Cov.: 27 AF XY: 0.000191 AC XY: 58 AN XY: 303252

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

African (AFR) AF: 0.000608 AC: 15 AN: 24667

American (AMR) AF: 0.0000590 AC: 2 AN: 33921

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18418

East Asian (EAS) AF: 0.0000723 AC: 2 AN: 27648

South Asian (SAS) AF: 0.00196 AC: 101 AN: 51456

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39080

Middle Eastern (MID) AF: 0.000332 AC: 1 AN: 3015

European-Non Finnish (NFE) AF: 0.000149 AC: 113 AN: 760617

Other (OTH) AF: 0.000259 AC: 11 AN: 42474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000280 AC: 18 AN: 64356 Hom.: 0 Cov.: 9 AF XY: 0.000445 AC XY: 5 AN XY: 11236

African (AFR) AF: 0.000241 AC: 5 AN: 20788

American (AMR) AF: 0.000728 AC: 4 AN: 5498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1553

East Asian (EAS) AF: 0.00 AC: 0 AN: 1499

South Asian (SAS) AF: 0.00466 AC: 5 AN: 1072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2751

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 117

European-Non Finnish (NFE) AF: 0.000101 AC: 3 AN: 29827

Other (OTH) AF: 0.00131 AC: 1 AN: 766

Alfa AF: 0.000336 Hom.: 2

ExAC AF: 0.0000606 AC: 7

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.5
DANN	Benign	0.69
DEOGEN2	Benign	0.0067	T
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.00084	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.60
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.067
Sift	Benign	0.060	T
Sift4G	Benign	0.79	T
Polyphen		0.70	P
Vest4		0.042
MutPred		0.61		Loss of loop (P = 0.1258)
MVP		0.14
MPC		2.7
ClinPred		0.066	T
Varity_R		0.43
gMVP		0.0024
Mutation Taster		=100/0	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: rs199904329; hg19: chrX-140335680; COSMIC: COSV99082078;