Genetic Variant NM_022661.4:c.89G>C (chrX-141241722-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022661.4(SPANXC):c.89G>C(p.Ser30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 31 hom., 21 hem., cov: 0)

Exomes 𝑓: 0.0050 ( 473 hom. 510 hem. )

Failed GnomAD Quality Control

Consequence

SPANXC
NM_022661.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.75

Publications

0 publications found

Variant links:

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]

SPANXC links:

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

SPANXA2-OT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071487427).

BS2

High Homozygotes in GnomAd4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPANXC	NM_022661.4 link	c.89G>C	p.Ser30Thr	missense_variant	Exon 2 of 2	ENST00000358993.3	NP_073152.2	Q9NY87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPANXC	ENST00000358993.3 link	c.89G>C	p.Ser30Thr	missense_variant	Exon 2 of 2	1	NM_022661.4	ENSP00000351884.2		Q9NY87
SPANXA2-OT1	ENST00000662492.1 link	n.102+53885C>G		intron_variant	Intron 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

583

AN:

43616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

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:

0.000408

Gnomad OTH

AF:

0.0121

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00498

AC:

2271

AN:

456312

Hom.:

473

Cov.:

AF XY:

0.00495

AC XY:

510

AN XY:

103074

show subpopulations

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

African (AFR)

AF:

0.0840

AC:

1411

AN:

16803

American (AMR)

AF:

0.00982

AC:

190

AN:

19356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8611

East Asian (EAS)

AF:

0.00

AC:

AN:

11152

South Asian (SAS)

AF:

0.000470

AC:

AN:

21278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18846

Middle Eastern (MID)

AF:

0.0217

AC:

AN:

1289

European-Non Finnish (NFE)

AF:

0.00115

AC:

388

AN:

338735

Other (OTH)

AF:

0.0121

AC:

244

AN:

20242

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0134

AC:

586

AN:

43641

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

AN XY:

9119

show subpopulations

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

African (AFR)

AF:

0.0389

AC:

554

AN:

14246

American (AMR)

AF:

0.00450

AC:

AN:

3996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1119

East Asian (EAS)

AF:

0.00

AC:

AN:

717

South Asian (SAS)

AF:

0.00

AC:

AN:

795

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000408

AC:

AN:

19594

Other (OTH)

AF:

0.0120

AC:

AN:

498

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.391

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.511

Hom.:

6056

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.15

(source)

DEOGEN2

Benign

0.0069

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0071

PhyloP100

-1.7

Sift4G

Benign

0.91

Vest4

0.10

gMVP

0.0024

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over