Genetic Variant SPANXN3:p.Thr44Ile (chrX-143509110-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001009609.4(SPANXN3):c.131C>T(p.Thr44Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,209,703 control chromosomes in the GnomAD database, including 1 homozygotes. There are 85 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 0.00018 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 1 hom. 78 hem. )

Consequence

SPANXN3
NM_001009609.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020703316).

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPANXN3	NM_001009609.4 link	c.131C>T	p.Thr44Ile	missense_variant	Exon 2 of 2	ENST00000370503.2	NP_001009609.2	Q5MJ09
SPANXN3	XM_017029264.2 link	c.128C>T	p.Thr43Ile	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.131C>T	p.Thr44Ile	missense_variant	Exon 2 of 2	1	NM_001009609.4	ENSP00000359534.2		Q5MJ09
ENSG00000227303	ENST00000431432.1 link	n.269-499G>A		intron_variant	Intron 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

111826

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

34000

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000230

AC:

AN:

182940

Hom.:

AF XY:

0.000341

AC XY:

AN XY:

67466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

165

AN:

1097877

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

363247

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00160

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000980

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000736

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000179

AC:

AN:

111826

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

34000

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000949

Gnomad4 ASJ

AF:

0.00151

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00149

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000651

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131C>T (p.T44I) alteration is located in exon 2 (coding exon 2) of the SPANXN3 gene. This alteration results from a C to T substitution at nucleotide position 131, causing the threonine (T) at amino acid position 44 to be replaced by an isoleucine (I). 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

0.24

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.9

DANN

Benign

0.97

FATHMM_MKL

Benign

0.0027

M_CAP

Benign

0.0018

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.30

Sift4G

Uncertain

0.035

Vest4

0.097

MVP

0.068

MPC

0.13

ClinPred

0.050

GERP RS

-4.8

gMVP

0.010

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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