X-145247648-A-G

Variant names:

• chrX-145247648-A-G
• rs147948245
• NM_001009614.3:c.62A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001009614.3(SPANXN1):​c.62A>G​(p.Asn21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000473 in 1,205,595 control chromosomes in the GnomAD database, including 1 homozygotes. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000027 (1 hom. 6 hem.)
• Consequence: SPANXN1 NM_001009614.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.272

Genes affected

SPANXN1 (HGNC:33174): (SPANX family member N1) This gene represents one of several duplicated family members that are located on chromosome X. This gene family encodes proteins that play a role in spermiogenesis. These proteins represent a specific subgroup of cancer/testis-associated antigens, and they may be candidates for tumor vaccines. This family member belongs to a subgroup of related genes that are present in all primates and rats and mice, and thus, it represents one of the ancestral family members. [provided by RefSeq, May 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010796189).
• BS2: High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPANXN1	NM_001009614.3	c.62A>G	p.Asn21Ser	missense_variant	Exon 1 of 2	ENST00000370493.4	NP_001009614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPANXN1	ENST00000370493.4	c.62A>G	p.Asn21Ser	missense_variant	Exon 1 of 2	1	NM_001009614.3	ENSP00000359524.3

Frequencies

GnomAD3 genomes AF: 0.000242 AC: 27 AN: 111390 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 22 AN: 183459 AF XY: 0.000103

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 30 AN: 1094153 Hom.: 1 Cov.: 29 AF XY: 0.0000167 AC XY: 6 AN XY: 359743

African (AFR) AF: 0.000570 AC: 15 AN: 26303

American (AMR) AF: 0.000199 AC: 7 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.00 AC: 0 AN: 54069

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40483

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4115

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838556

Other (OTH) AF: 0.000174 AC: 8 AN: 45945

GnomAD4 genome AF: 0.000242 AC: 27 AN: 111442 Hom.: 0 Cov.: 23 AF XY: 0.000268 AC XY: 9 AN XY: 33630

African (AFR) AF: 0.000653 AC: 20 AN: 30627

American (AMR) AF: 0.000665 AC: 7 AN: 10528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53067

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.000170 Hom.: 2

Bravo AF: 0.000351

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62A>G (p.N21S) alteration is located in exon 1 (coding exon 1) of the SPANXN1 gene. This alteration results from a A to G substitution at nucleotide position 62, causing the asparagine (N) at amino acid position 21 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.93	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.58
DANN	Benign	0.49
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.00069	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.27
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.045
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.0070	B
Vest4		0.070
MVP		0.093
MPC		0.0040
ClinPred		0.0020	T
PromoterAI		-0.093	Neutral
Varity_R		0.078
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

Publications

LitVar

Other links and lift over

dbSNP: rs147948245; hg19: chrX-144329168;