Variant 1-15935976-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_015001.3(SPEN):c.9736A>G(p.Thr3246Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 650,580 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. T3246P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.543

Variant links:

Genes affected

SPEN (HGNC:17575): (spen family transcriptional repressor) This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors. [provided by RefSeq, Jul 2008]

SPEN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP2

Missense variant where missense usually causes diseases, SPEN

BP4

Computational evidence support a benign effect (MetaRNN=0.02224642).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000706 (42/595192) while in subpopulation NFE AF= 0.0000882 (39/442058). AF 95% confidence interval is 0.000066. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEN	NM_015001.3 linkuse as main transcript	c.9736A>G	p.Thr3246Ala	missense_variant	11/15	ENST00000375759.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPEN	ENST00000375759.8 linkuse as main transcript	c.9736A>G	p.Thr3246Ala	missense_variant	11/15	1	NM_015001.3	P1
SPEN	ENST00000704274.1 linkuse as main transcript	c.5335A>G	p.Thr1779Ala	missense_variant	1/4
SPEN	ENST00000438066.2 linkuse as main transcript	c.*10587A>G		3_prime_UTR_variant, NMD_transcript_variant	11/15	3

Frequencies

GnomAD3 genomes

AF:

0.0000361

AC:

AN:

55388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000789

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

AN:

595192

Hom.:

Cov.:

AF XY:

0.0000535

AC XY:

AN XY:

298870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000562

Gnomad4 SAS exome

AF:

0.0000258

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000882

Gnomad4 OTH exome

AF:

0.0000405

GnomAD4 genome

AF:

0.0000361

AC:

AN:

55388

Hom.:

Cov.:

AF XY:

0.0000748

AC XY:

AN XY:

26752

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000789

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000864

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0070

DANN

Benign

0.10

DEOGEN2

Benign

0.10

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.24

M_CAP

Benign

0.0050

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

0.14

REVEL

Benign

0.015

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.042

MutPred

0.20

Loss of glycosylation at T3246 (P = 1e-04);

MVP

0.043

MPC

0.23

ClinPred

0.019

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.022

gMVP

0.072

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over