X-135906501-G-A

Variant names:

• chrX-135906501-G-A
• rs781926163
• NM_001381902.1:c.686G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001381902.1(SAGE1):​c.686G>A​(p.Arg229His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,208,952 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 28)
  • Exomes 𝑓: 0.000017 (0 hom. 3 hem.)
• Consequence: SAGE1 NM_001381902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.675
• Publications: 3 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.061539143).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001381902.1. 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
	SAGE1	NM_001381902.1	MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 20	NP_001368831.1	Q9NXZ1
	SAGE1	NM_018666.3		c.686G>A	p.Arg229His	missense	Exon 7 of 20	NP_061136.2	Q9NXZ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAGE1	ENST00000370709.4	TSL:5 MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 20	ENSP00000359743.3	Q9NXZ1
	SAGE1	ENST00000324447.8	TSL:5	c.686G>A	p.Arg229His	missense	Exon 7 of 20	ENSP00000323191.3	Q9NXZ1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112545 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182342 AF XY: 0.0000150

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1096407 Hom.: 0 Cov.: 30 AF XY: 0.00000829 AC XY: 3 AN XY: 361847

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.00 AC: 0 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 53929

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 840762

Other (OTH) AF: 0.00 AC: 0 AN: 46026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000117984), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112545 Hom.: 0 Cov.: 28 AF XY: 0.0000576 AC XY: 2 AN XY: 34703

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30914

American (AMR) AF: 0.000188 AC: 2 AN: 10614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53319

Other (OTH) AF: 0.00 AC: 0 AN: 1521

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000540 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.83
DEOGEN2	Benign	0.0084	T
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.68
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.010
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.0060	B
Vest4		0.11
MVP		0.18
ClinPred		0.028	T
GERP RS		-0.13
Varity_R		0.024
gMVP		0.024
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs781926163; hg19: chrX-134988660; COSMIC: COSV61017933;