6-34541114-C-G

Variant names:

• chr6-34541114-C-G
• rs2233643
• NM_012391.3:c.504G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_012391.3(SPDEF):​c.504G>C​(p.Leu168Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,610,388 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: SPDEF NM_012391.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-34541114-C-G is Benign according to our data. Variant chr6-34541114-C-G is described in ClinVar as Benign. ClinVar VariationId is 783752.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00691 (1053/152322) while in subpopulation AFR AF = 0.0241 (1001/41578). AF 95% confidence interval is 0.0228. There are 14 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 gene

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.504G>C	p.Leu168Leu	synonymous	Exon 3 of 6	NP_036523.1	O95238-1
	SPDEF	NM_001252294.2		c.504G>C	p.Leu168Leu	synonymous	Exon 3 of 5	NP_001239223.1	O95238-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDEF	ENST00000374037.8	TSL:1 MANE Select	c.504G>C	p.Leu168Leu	synonymous	Exon 3 of 6	ENSP00000363149.3	O95238-1
	SPDEF	ENST00000886645.1		c.504G>C	p.Leu168Leu	synonymous	Exon 3 of 6	ENSP00000556704.1
	SPDEF	ENST00000943125.1		c.585G>C	p.Leu195Leu	synonymous	Exon 4 of 7	ENSP00000613184.1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152204 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

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: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00158 AC: 381 AN: 240870 AF XY: 0.00112

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.000681

GnomAD4 exome AF: 0.000623 AC: 909 AN: 1458066 Hom.: 7 Cov.: 31 AF XY: 0.000505 AC XY: 366 AN XY: 724974

African (AFR) AF: 0.0216 AC: 721 AN: 33426

American (AMR) AF: 0.00153 AC: 68 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52686

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1110772

Other (OTH) AF: 0.00150 AC: 90 AN: 60176

GnomAD4 genome AF: 0.00691 AC: 1053 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00689 AC XY: 513 AN XY: 74492

African (AFR) AF: 0.0241 AC: 1001 AN: 41578

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00767

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		3.1
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2233643; hg19: chr6-34508891;