X-151722682-C-A

Variant names:

• chrX-151722682-C-A
• rs777906779
• NM_033085.3:c.475C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033085.3(FATE1):​c.475C>A​(p.Arg159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: FATE1 NM_033085.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.759

Genes affected

FATE1 (HGNC:24683): (fetal and adult testis expressed 1) This gene encodes a cancer-testis antigen that is highly expressed in hepatocellular carcinomas and other tumors and weakly expressed in normal tissues except testis. The protein is strongly expressed in spermatogonia, primary spermatocytes, and Sertoli cells in seminiferous tubules. This protein may have a role in the control of early testicular differentiation and cell proliferation. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14200014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FATE1	NM_033085.3	c.475C>A	p.Arg159Ser	missense_variant	Exon 5 of 5	ENST00000370350.7	NP_149076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FATE1	ENST00000370350.7	c.475C>A	p.Arg159Ser	missense_variant	Exon 5 of 5	1	NM_033085.3	ENSP00000359375.3
FATE1	ENST00000417321.1	c.*101C>A		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000400493.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000165 AC: 3 AN: 181784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66934

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097798 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363206

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475C>A (p.R159S) alteration is located in exon 5 (coding exon 5) of the FATE1 gene. This alteration results from a C to A substitution at nucleotide position 475, causing the arginine (R) at amino acid position 159 to be replaced by a serine (S). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.038
Sift	Benign	0.054	T
Sift4G	Benign	0.082	T
Polyphen		0.92	P
Vest4		0.068
MutPred		0.25		Loss of MoRF binding (P = 0.0367);
MVP		0.82
MPC		0.15
ClinPred		0.36	T
GERP RS		-0.76
Varity_R		0.37
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777906779; hg19: chrX-150891154;