Genetic Variant SPDEF:p.His225Arg (chr6-34539523-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056390315).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012391.3. 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
	SPDEF	NM_012391.3	MANE Select	c.674A>G	p.His225Arg	missense	Exon 4 of 6	NP_036523.1	O95238-1
	SPDEF	NM_001252294.2		c.635-127A>G		intron	N/A	NP_001239223.1	O95238-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDEF	ENST00000374037.8	TSL:1 MANE Select	c.674A>G	p.His225Arg	missense	Exon 4 of 6	ENSP00000363149.3	O95238-1
SPDEF	ENST00000886645.1		c.815A>G	p.His272Arg	missense	Exon 4 of 6	ENSP00000556704.1
SPDEF	ENST00000943125.1		c.755A>G	p.His252Arg	missense	Exon 5 of 7	ENSP00000613184.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000106

AC:

AN:

187964

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1423912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704992

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32648

American (AMR)

AF:

0.00

AC:

AN:

39508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

37574

South Asian (SAS)

AF:

0.00

AC:

AN:

82034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4616

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093754

Other (OTH)

AF:

0.00

AC:

AN:

58828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000251

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.062

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.46

M_CAP

Benign

0.0031

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.44

PhyloP100

2.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.080

REVEL

Benign

0.062

Sift

Benign

0.62

Sift4G

Benign

0.57

Polyphen

0.0010

Vest4

0.062

MVP

0.043

MPC

0.31

ClinPred

0.023

GERP RS

5.2

Varity_R

0.11

gMVP

0.11

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over