6-34544224-G-A

Variant names:

• chr6-34544224-G-A
• rs143236716
• NM_012391.3:c.232C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012391.3(SPDEF):​c.232C>T​(p.Pro78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P78L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SPDEF NM_012391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073479146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDEF	NM_012391.3	c.232C>T	p.Pro78Ser	missense_variant	Exon 2 of 6	ENST00000374037.8	NP_036523.1
SPDEF	NM_001252294.2	c.232C>T	p.Pro78Ser	missense_variant	Exon 2 of 5		NP_001239223.1
SPDEF	XM_005248988.6	c.448C>T	p.Pro150Ser	missense_variant	Exon 2 of 6		XP_005249045.2
SPDEF	XM_011514457.4	c.448C>T	p.Pro150Ser	missense_variant	Exon 2 of 4		XP_011512759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDEF	ENST00000374037.8	c.232C>T	p.Pro78Ser	missense_variant	Exon 2 of 6	1	NM_012391.3	ENSP00000363149.3
SPDEF	ENST00000544425.2	c.232C>T	p.Pro78Ser	missense_variant	Exon 2 of 5	2		ENSP00000442715.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250440 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

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: 0.000177

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.000237 AC XY: 172 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

Gnomad4 AFR AF: 0.0000723

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: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232C>T (p.P78S) alteration is located in exon 2 (coding exon 1) of the SPDEF gene. This alteration results from a C to T substitution at nucleotide position 232, causing the proline (P) at amino acid position 78 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.28
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.056
Sift	Benign	0.55	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0020	B;.
Vest4		0.079
MVP		0.068
MPC		0.29
ClinPred		0.033	T
GERP RS		4.2
Varity_R		0.032
gMVP		0.16

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

Other links and lift over

dbSNP: rs143236716; hg19: chr6-34512001; COSMIC: COSV105300582;