rs769360962

Variant names:

• chr1-15935976-A-C
• rs769360962
• NM_015001.3:c.9736A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-15935976-A-C
• chr1-15935976-A-G
• chr1-15935976-A-T

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.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. 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. T3246N) 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:3
• Conservation: PhyloP100: -0.543
• Publications: 10 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=0.0016164482).
• BP6: Variant 1-15935976-A-C is Benign according to our data. Variant chr1-15935976-A-C is described in ClinVar as Benign. ClinVar VariationId is 403486.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.9736A>C	p.Thr3246Pro	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.9736A>C	p.Thr3246Pro	missense_variant	Exon 11 of 15	1	NM_015001.3	ENSP00000364912.3
SPEN	ENST00000704274.1	c.5332A>C	p.Thr1778Pro	missense_variant	Exon 1 of 4			ENSP00000515812.1
SPEN	ENST00000438066.2	n.*10587A>C		non_coding_transcript_exon_variant	Exon 11 of 15	3		ENSP00000388021.2
SPEN	ENST00000438066.2	n.*10587A>C		3_prime_UTR_variant	Exon 11 of 15	3		ENSP00000388021.2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 9353 AN: 39114 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.0527 AC: 4278 AN: 81104 AF XY: 0.0515

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.0775

Gnomad OTH exome AF: 0.0247

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

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

African (AFR) AF: 0.0446 AC: 396 AN: 8880

American (AMR) AF: 0.00706 AC: 153 AN: 21686

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 182 AN: 7230

East Asian (EAS) AF: 0.0126 AC: 158 AN: 12502

South Asian (SAS) AF: 0.0259 AC: 713 AN: 27512

European-Finnish (FIN) AF: 0.0600 AC: 779 AN: 12984

Middle Eastern (MID) AF: 0.0417 AC: 40 AN: 960

European-Non Finnish (NFE) AF: 0.0856 AC: 19250 AN: 224806

Other (OTH) AF: 0.0552 AC: 771 AN: 13958

⚠️ 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: 0.239 AC: 9356 AN: 39150 Hom.: 0 Cov.: 0 AF XY: 0.225 AC XY: 4295 AN XY: 19128

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

African (AFR) AF: 0.232 AC: 2420 AN: 10420

American (AMR) AF: 0.213 AC: 874 AN: 4108

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 266 AN: 982

East Asian (EAS) AF: 0.160 AC: 161 AN: 1006

South Asian (SAS) AF: 0.161 AC: 172 AN: 1066

European-Finnish (FIN) AF: 0.155 AC: 472 AN: 3044

Middle Eastern (MID) AF: 0.111 AC: 6 AN: 54

European-Non Finnish (NFE) AF: 0.271 AC: 4799 AN: 17706

Other (OTH) AF: 0.261 AC: 148 AN: 566

⚠️ 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: 0.0143 Hom.: 0

ExAC AF: 0.0248 AC: 2869

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

Mar 29, 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	0.086
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
PhyloP100		-0.54
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
Mutation Taster		=92/8	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: rs769360962; hg19: chr1-16262471; COSMIC: COSV65357339; COSMIC: COSV65357339;