Genetic Variant SAGE1:p.Pro132Ser (chrX-135905332-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001381902.1(SAGE1):c.394C>T(p.Pro132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,207,281 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P132L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 7 hem. )

Consequence

SAGE1
NM_001381902.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.542

Variant links:

Genes affected

SAGE1 (HGNC:30369): (sarcoma antigen 1) This gene belongs to a class of genes that are activated in tumors. These genes are expressed in tumors of different histologic types but not in normal tissues, except for spermatogenic cells and, for some, placenta. The proteins encoded by these genes appear to be strictly tumor specific, and hence may be excellent sources of antigens for cancer immunotherapy. This gene is expressed in sarcomas. [provided by RefSeq, Jul 2008]

SAGE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021121621).

BP6

Variant X-135905332-C-T is Benign according to our data. Variant chrX-135905332-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3316018.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAGE1	NM_001381902.1 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 5 of 20	ENST00000370709.4	NP_001368831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAGE1	ENST00000370709.4 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 5 of 20	5	NM_001381902.1	ENSP00000359743.3		Q9NXZ1
SAGE1	ENST00000324447.8 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 5 of 20	5		ENSP00000323191.3		Q9NXZ1

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111621

Hom.:

Cov.:

AF XY:

0.000236

AC XY:

AN XY:

33845

show subpopulations

Gnomad AFR

AF:

0.000684

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000546

AC:

AN:

183259

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

67735

show subpopulations

Gnomad AFR exome

AF:

0.000760

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1095607

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361063

show subpopulations

Gnomad4 AFR exome

AF:

0.000531

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.000188

AC:

AN:

111674

Hom.:

Cov.:

AF XY:

0.000236

AC XY:

AN XY:

33908

show subpopulations

Gnomad4 AFR

AF:

0.000683

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.1

DANN

Benign

0.97

DEOGEN2

Benign

0.018

T;T;T

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.34

T;T;.

M_CAP

Benign

0.0013

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

N;D;N

REVEL

Benign

0.039

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.081

T;T;T

Polyphen

1.0

D;B;D

Vest4

0.15

MVP

0.16

ClinPred

0.017

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.053

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