chr1-15935970-A-C

Variant names:

• chr1-15935970-A-C
• rs776474446
• NM_015001.3:c.9730A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. 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. 15/21 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 NM_015001.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.451
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Radio-Tartaglia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• 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 VariationId is 403485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEN	NM_015001.3	c.9730A>C	p.Thr3244Pro	missense_variant	Exon 11 of 15	ENST00000375759.8	NP_055816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEN	ENST00000375759.8	c.9730A>C	p.Thr3244Pro	missense_variant	Exon 11 of 15	1	NM_015001.3	ENSP00000364912.3
SPEN	ENST00000704274.1	c.5326A>C	p.Thr1776Pro	missense_variant	Exon 1 of 4			ENSP00000515812.1
SPEN	ENST00000438066.2	n.*10581A>C		non_coding_transcript_exon_variant	Exon 11 of 15	3		ENSP00000388021.2
SPEN	ENST00000438066.2	n.*10581A>C		3_prime_UTR_variant	Exon 11 of 15	3		ENSP00000388021.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 11775 AN: 52116 Hom.: 0 Cov.: 9

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

GnomAD2 exomes AF: 0.0395 AC: 4399 AN: 111310 AF XY: 0.0384

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.0187

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0849 AC: 1053 AN: 12406

American (AMR) AF: 0.0116 AC: 296 AN: 25626

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 453 AN: 10042

East Asian (EAS) AF: 0.0257 AC: 397 AN: 15462

South Asian (SAS) AF: 0.0315 AC: 1414 AN: 44838

European-Finnish (FIN) AF: 0.0844 AC: 1534 AN: 18170

Middle Eastern (MID) AF: 0.0837 AC: 114 AN: 1362

European-Non Finnish (NFE) AF: 0.152 AC: 50784 AN: 333148

Other (OTH) AF: 0.100 AC: 1985 AN: 19806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.219 AC: 3072 AN: 14036

American (AMR) AF: 0.225 AC: 1108 AN: 4934

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 325 AN: 1304

East Asian (EAS) AF: 0.166 AC: 249 AN: 1502

South Asian (SAS) AF: 0.172 AC: 249 AN: 1450

European-Finnish (FIN) AF: 0.195 AC: 665 AN: 3418

Middle Eastern (MID) AF: 0.167 AC: 12 AN: 72

European-Non Finnish (NFE) AF: 0.241 AC: 5853 AN: 24316

Other (OTH) AF: 0.239 AC: 176 AN: 736

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.185 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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SPEN-related disorder Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.45
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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

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