1-15935970-A-C

Position:

chr1-15935970-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The ENST00000375759.8(SPEN):c.9730A>C(p.Thr3244Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3244A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.23 ( 0 hom., cov: 9)

Exomes 𝑓: 0.12 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPEN
ENST00000375759.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.451

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPEN. . Gene score misZ 2.8932 (greater than the threshold 3.09). Trascript score misZ 5.0985 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, Radio-Tartaglia syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022108853).

BP6

Variant 1-15935970-A-C is Benign according to our data. Variant chr1-15935970-A-C is described in ClinVar as [Benign]. Clinvar id is 403485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEN	NM_015001.3 linkuse as main transcript	c.9730A>C	p.Thr3244Pro	missense_variant	11/15	ENST00000375759.8	NP_055816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SPEN	ENST00000375759.8 linkuse as main transcript	c.9730A>C	p.Thr3244Pro	missense_variant	11/15	1	NM_015001.3	ENSP00000364912	P1
SPEN	ENST00000704274.1 linkuse as main transcript	c.5329A>C	p.Thr1777Pro	missense_variant	1/4			ENSP00000515812
SPEN	ENST00000438066.2 linkuse as main transcript	c.*10581A>C		3_prime_UTR_variant, NMD_transcript_variant	11/15	3		ENSP00000388021

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

11775

AN:

52116

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.154

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.240

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.121

AC:

58030

AN:

480860

Hom.:

Cov.:

AF XY:

0.109

AC XY:

27060

AN XY:

248002

show subpopulations

Gnomad4 AFR exome

AF:

0.0849

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.0451

Gnomad4 EAS exome

AF:

0.0257

Gnomad4 SAS exome

AF:

0.0315

Gnomad4 FIN exome

AF:

0.0844

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff

AF:

0.226

AC:

11773

AN:

52112

Hom.:

Cov.:

AF XY:

0.219

AC XY:

5411

AN XY:

24762

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.225

Gnomad4 ASJ

AF:

0.249

Gnomad4 EAS

AF:

0.166

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.195

Gnomad4 NFE

AF:

0.241

Gnomad4 OTH

AF:

0.239

Alfa

AF:

0.345

Hom.:

ExAC

AF:

0.0224

AC:

2552

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Fails ExAC quality filter -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

SPEN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.9

DANN

Benign

0.17

DEOGEN2

Benign

0.088

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.22

REVEL

Benign

0.017

Sift

Uncertain

0.024

Sift4G

Benign

0.25

Polyphen

0.0040

Vest4

0.057

MPC

0.30

ClinPred

0.00058

GERP RS

-0.36

Varity_R

0.067

gMVP

0.089

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over