rs776474446

Positions:

• chr1-15935970-A-C
• chr1-15935970-A-G
• chr1-15935970-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.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 (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (0 hom., cov: 9)
  • Exomes 𝑓: 0.12 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPEN NM_015001.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.451

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 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	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	UniProt
SPEN	ENST00000375759.8	c.9730A>C	p.Thr3244Pro	missense_variant	11/15	1	NM_015001.3	ENSP00000364912	P1
SPEN	ENST00000704274.1	c.5329A>C	p.Thr1777Pro	missense_variant	1/4			ENSP00000515812
SPEN	ENST00000438066.2	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.: 0 Cov.: 9 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.: 0 Cov.: 35 AF XY: 0.109 AC XY: 27060 AN XY: 248002

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.: 0 Cov.: 9 AF XY: 0.219 AC XY: 5411 AN XY: 24762

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.: 0

ExAC AF: 0.0224 AC: 2552

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 -

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	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.17
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.017
Sift	Uncertain	0.024	D
Sift4G	Benign	0.25	T
Polyphen		0.0040	B
Vest4		0.057
MPC		0.30
ClinPred		0.00058	T
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

Other links and lift over

dbSNP: rs776474446; hg19: chr1-16262465; COSMIC: COSV65357150; COSMIC: COSV65357150;