6-34539544-C-T

Variant names:

• chr6-34539544-C-T
• rs201096048
• NM_012391.3:c.653G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012391.3(SPDEF):​c.653G>A​(p.Arg218Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,572,866 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SPDEF NM_012391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.497

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]

ACMG classification

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=0.007796526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDEF	NM_012391.3	c.653G>A	p.Arg218Gln	missense_variant	Exon 4 of 6	ENST00000374037.8	NP_036523.1
SPDEF	XM_005248988.6	c.869G>A	p.Arg290Gln	missense_variant	Exon 4 of 6		XP_005249045.2
SPDEF	NM_001252294.2	c.635-148G>A		intron_variant	Intron 3 of 4		NP_001239223.1
SPDEF	XM_011514457.4	c.*177G>A		downstream_gene_variant			XP_011512759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDEF	ENST00000374037.8	c.653G>A	p.Arg218Gln	missense_variant	Exon 4 of 6	1	NM_012391.3	ENSP00000363149.3
SPDEF	ENST00000544425.2	c.635-148G>A		intron_variant	Intron 3 of 4	2		ENSP00000442715.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000309

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000245 AC: 45 AN: 183796 Hom.: 0 AF XY: 0.000201 AC XY: 20 AN XY: 99310

Gnomad AFR exome AF: 0.0000987

Gnomad AMR exome AF: 0.000959

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: 0.000183

Gnomad OTH exome AF: 0.000624

GnomAD4 exome AF: 0.000214 AC: 304 AN: 1420534 Hom.: 0 Cov.: 35 AF XY: 0.000219 AC XY: 154 AN XY: 702960

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000841

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: 0.000236

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000461 AC: 2

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000151 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.653G>A (p.R218Q) alteration is located in exon 4 (coding exon 3) of the SPDEF gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a glutamine (Q). 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	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.047
Sift	Benign	0.24	T
Sift4G	Benign	0.57	T
Polyphen		0.91	P
Vest4		0.18
MVP		0.17
MPC		0.37
ClinPred		0.015	T
GERP RS		5.4
Varity_R		0.063
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs201096048; hg19: chr6-34507321;