Genetic Variant SPANXN3:p.Met27Leu (chrX-143509162-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001009609.4(SPANXN3):c.79A>T(p.Met27Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,197,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00013 ( 0 hom. 45 hem. )

Consequence

SPANXN3
NM_001009609.4 missense, splice_region

Scores

Splicing: ADA: 0.0002984

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.286

Publications

1 publications found

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 was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.00783056).

BS2

High Hemizygotes in GnomAdExome4 at 45 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009609.4. 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
	SPANXN3	NM_001009609.4	MANE Select	c.79A>T	p.Met27Leu	missense splice_region	Exon 2 of 2	NP_001009609.2	Q5MJ09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPANXN3	ENST00000370503.2	TSL:1 MANE Select	c.79A>T	p.Met27Leu	missense splice_region	Exon 2 of 2	ENSP00000359534.2	Q5MJ09
	ENSG00000227303	ENST00000431432.1	TSL:3	n.269-447T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00492

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000277

AC:

AN:

173359

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00600

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000641

Gnomad OTH exome

AF:

0.000945

GnomAD4 exome

AF:

0.000133

AC:

145

AN:

1086215

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

353119

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26081

American (AMR)

AF:

0.00

AC:

AN:

34579

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

100

AN:

18758

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00

AC:

AN:

52397

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40148

Middle Eastern (MID)

AF:

0.000254

AC:

AN:

3936

European-Non Finnish (NFE)

AF:

0.0000312

AC:

AN:

834617

Other (OTH)

AF:

0.000395

AC:

AN:

45551

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000125

AC:

AN:

111728

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30636

American (AMR)

AF:

0.00

AC:

AN:

10488

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2651

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6101

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53236

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.579

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:

0.000738

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000198

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.6

(source)

DANN

Benign

0.47

FATHMM_MKL

Benign

0.026

M_CAP

Benign

0.00090

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.1

PhyloP100

0.29

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

REVEL

Benign

0.10

Sift

Benign

0.16

Sift4G

Benign

0.36

Vest4

0.15

MutPred

0.75

Gain of helix (P = 0.132)

MVP

0.068

MPC

0.057

ClinPred

0.044

GERP RS

-3.1

gMVP

0.0054

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.024

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over