Genetic Variant SPDEF:p.Ser187Leu (chr6-34541058-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012391.3(SPDEF):c.560C>T(p.Ser187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SPDEF
NM_012391.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

Variant links:

Genes affected

SPDEF (HGNC:17257): (SAM pointed domain containing ETS transcription factor) The protein encoded by this gene belongs to the ETS family of transcription factors. It is highly expressed in the prostate epithelial cells, and functions as an androgen-independent transactivator of prostate-specific antigen (PSA) promoter. Higher expression of this protein has also been reported in brain, breast, lung and ovarian tumors, compared to the corresponding normal tissues, and it shows better tumor-association than other cancer-associated molecules, making it a more suitable target for developing specific cancer therapies. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

SPDEF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDEF	NM_012391.3 link	c.560C>T	p.Ser187Leu	missense_variant	Exon 3 of 6	ENST00000374037.8	NP_036523.1	O95238-1
SPDEF	NM_001252294.2 link	c.560C>T	p.Ser187Leu	missense_variant	Exon 3 of 5		NP_001239223.1	O95238-2
SPDEF	XM_005248988.6 link	c.776C>T	p.Ser259Leu	missense_variant	Exon 3 of 6		XP_005249045.2
SPDEF	XM_011514457.4 link	c.776C>T	p.Ser259Leu	missense_variant	Exon 3 of 4		XP_011512759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDEF	ENST00000374037.8 link	c.560C>T	p.Ser187Leu	missense_variant	Exon 3 of 6	1	NM_012391.3	ENSP00000363149.3		O95238-1
SPDEF	ENST00000544425.2 link	c.560C>T	p.Ser187Leu	missense_variant	Exon 3 of 5	2		ENSP00000442715.1		O95238-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

247582

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000285

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460270

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726428

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560C>T (p.S187L) alteration is located in exon 3 (coding exon 2) of the SPDEF gene. This alteration results from a C to T substitution at nucleotide position 560, causing the serine (S) at amino acid position 187 to be replaced by a leucine (L). 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

0.30

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.86

P;.

Vest4

0.82

MutPred

0.63

Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);

MVP

0.15

MPC

0.70

ClinPred

0.86

GERP RS

5.7

Varity_R

0.51

gMVP

0.55

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