X-135905354-C-T

Variant names:

• chrX-135905354-C-T
• rs2088767955
• NM_001381902.1:c.416C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001381902.1(SAGE1):​c.416C>T​(p.Ala139Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000913 in 1,095,589 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 6 hem.)
• Consequence: SAGE1 NM_001381902.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122632384).
• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAGE1	NM_001381902.1	c.416C>T	p.Ala139Val	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	c.416C>T	p.Ala139Val	missense_variant	Exon 5 of 20	5	NM_001381902.1	ENSP00000359743.3
SAGE1	ENST00000324447.8	c.416C>T	p.Ala139Val	missense_variant	Exon 5 of 20	5		ENSP00000323191.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000913 AC: 10 AN: 1095589 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 6 AN XY: 361067

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: 0.000167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416C>T (p.A139V) alteration is located in exon 5 (coding exon 4) of the SAGE1 gene. This alteration results from a C to T substitution at nucleotide position 416, causing the alanine (A) at amino acid position 139 to be replaced by a valine (V). 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	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0081	T;T;T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.49	T;T;.
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.087	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.97	D;P;D
Vest4		0.26
MutPred		0.34		Gain of catalytic residue at A139 (P = 0.0401);Gain of catalytic residue at A139 (P = 0.0401);Gain of catalytic residue at A139 (P = 0.0401);
MVP		0.27
ClinPred		0.19	T
GERP RS		1.1
Varity_R		0.053
gMVP		0.038

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: rs2088767955; hg19: chrX-134987513;