6-34544227-C-T

Variant names:

• chr6-34544227-C-T
• NM_012391.3:c.229G>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.229G>A​(p.Ala77Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,506 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A77S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPDEF NM_012391.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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=0.063094735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDEF	NM_012391.3	c.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 6	ENST00000374037.8	NP_036523.1
SPDEF	NM_001252294.2	c.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 5		NP_001239223.1
SPDEF	XM_005248988.6	c.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 6		XP_005249045.2
SPDEF	XM_011514457.4	c.445G>A	p.Ala149Thr	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.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 6	1	NM_012391.3	ENSP00000363149.3
SPDEF	ENST00000544425.2	c.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 5	2		ENSP00000442715.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461506 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.036
Sift	Benign	0.15	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.094	B;.
Vest4		0.071
MutPred		0.23		Gain of phosphorylation at A77 (P = 0.0053);Gain of phosphorylation at A77 (P = 0.0053);
MVP		0.068
MPC		0.26
ClinPred		0.16	T
GERP RS		3.3
Varity_R		0.040
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-34512004;