Genetic Variant SPANXN3:p.Asp114Asn (chrX-143508901-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001009609.4(SPANXN3):c.340G>A(p.Asp114Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,209,899 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000048 ( 0 hom. 14 hem. )

Consequence

SPANXN3
NM_001009609.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0730

Variant links:

Genes affected

SPANXN3 (HGNC:33176): (SPANX family member N3)

SPANXN3 links:

ENSG00000227303 (HGNC:):

ENSG00000227303 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117563486).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPANXN3	NM_001009609.4 link	c.340G>A	p.Asp114Asn	missense_variant	Exon 2 of 2	ENST00000370503.2	NP_001009609.2	Q5MJ09
SPANXN3	XM_017029264.2 link	c.337G>A	p.Asp113Asn	missense_variant	Exon 2 of 2		XP_016884753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPANXN3	ENST00000370503.2 link	c.340G>A	p.Asp114Asn	missense_variant	Exon 2 of 2	1	NM_001009609.4	ENSP00000359534.2		Q5MJ09
ENSG00000227303	ENST00000431432.1 link	n.269-708C>T		intron_variant	Intron 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111863

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34033

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183242

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

67772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1098036

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

363396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000606

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111863

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34033

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.340G>A (p.D114N) alteration is located in exon 2 (coding exon 2) of the SPANXN3 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the aspartic acid (D) at amino acid position 114 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.0077

M_CAP

Benign

0.00098

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Benign

0.025

Sift

Uncertain

0.015

Sift4G

Uncertain

0.010

Vest4

0.090

MVP

0.068

MPC

0.13

ClinPred

0.15

GERP RS

0.42

gMVP

0.0032

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over