NM_012391.3:c.674A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012391.3(SPDEF):​c.674A>G​(p.His225Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,576,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SPDEF
NM_012391.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.056390315).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPDEFNM_012391.3 linkc.674A>G p.His225Arg missense_variant Exon 4 of 6 ENST00000374037.8 NP_036523.1 O95238-1
SPDEFXM_005248988.6 linkc.890A>G p.His297Arg missense_variant Exon 4 of 6 XP_005249045.2
SPDEFNM_001252294.2 linkc.635-127A>G intron_variant Intron 3 of 4 NP_001239223.1 O95238-2
SPDEFXM_011514457.4 linkc.*198A>G downstream_gene_variant XP_011512759.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPDEFENST00000374037.8 linkc.674A>G p.His225Arg missense_variant Exon 4 of 6 1 NM_012391.3 ENSP00000363149.3 O95238-1
SPDEFENST00000544425.2 linkc.635-127A>G intron_variant Intron 3 of 4 2 ENSP00000442715.1 O95238-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.0000106
AC:
2
AN:
187964
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
101930
show subpopulations
Gnomad AFR exome
AF:
0.000189
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:
7.02e-7
AC:
1
AN:
1423912
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
704992
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000121
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:
0.0000658
Hom.:
0
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.000232
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000251
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.674A>G (p.H225R) alteration is located in exon 4 (coding exon 3) of the SPDEF gene. This alteration results from a A to G substitution at nucleotide position 674, causing the histidine (H) at amino acid position 225 to be replaced by an arginine (R). 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
0.065
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
15
DANN
Benign
0.78
DEOGEN2
Benign
0.062
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.46
T
M_CAP
Benign
0.0031
T
MetaRNN
Benign
0.056
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.44
N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.080
N
REVEL
Benign
0.062
Sift
Benign
0.62
T
Sift4G
Benign
0.57
T
Polyphen
0.0010
B
Vest4
0.062
MVP
0.043
MPC
0.31
ClinPred
0.023
T
GERP RS
5.2
Varity_R
0.11
gMVP
0.11

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs377061561; hg19: chr6-34507300; API