rs769360962

chr1-15935976-A-Cchr1-15935976-A-Gchr1-15935976-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_015001.3(SPEN):c.9736A>C(p.Thr3246Pro) 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. T3246I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (0 hom., cov: 0)
  • Exomes 𝑓: 0.068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPEN NM_015001.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.543

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]

ACMG classification

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=0.0016164482).
• BP6: Variant 1-15935976-A-C is Benign according to our data. Variant chr1-15935976-A-C is described in ClinVar as [Benign]. Clinvar id is 403486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEN	NM_015001.3	c.9736A>C	p.Thr3246Pro	missense_variant	11/15	ENST00000375759.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEN	ENST00000375759.8	c.9736A>C	p.Thr3246Pro	missense_variant	11/15	1	NM_015001.3	P1
SPEN	ENST00000704274.1	c.5335A>C	p.Thr1779Pro	missense_variant	1/4
SPEN	ENST00000438066.2	c.*10587A>C		3_prime_UTR_variant, NMD_transcript_variant	11/15	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9353 AN: 39114 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0679 AC: 22442 AN: 330518 Hom.: 0 Cov.: 31 AF XY: 0.0621 AC XY: 10592 AN XY: 170696

Gnomad4 AFR exome AF: 0.0446

Gnomad4 AMR exome AF: 0.00706

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.0600

Gnomad4 NFE exome AF: 0.0856

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.239 AC: 9356 AN: 39150 Hom.: 0 Cov.: 0 AF XY: 0.225 AC XY: 4295 AN XY: 19128

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.261

Alfa AF: 0.0143 Hom.: 0

ExAC AF: 0.0248 AC: 2869

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 -

SPEN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 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	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.075
Dann	Benign	0.14
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.023
Sift	Benign	0.095	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.30
ClinPred		0.000027	T
GERP RS		-0.92
Varity_R		0.057
gMVP		0.084

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: rs769360962; hg19: chr1-16262471; COSMIC: COSV65357339; COSMIC: COSV65357339;