Genetic Variant SPEN:p.Thr3246Ser (chr1-15935976-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015001.3(SPEN):c.9736A>T(p.Thr3246Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3246P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.543

Publications

10 publications found

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 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

SPEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02856204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEN	NM_015001.3 link	c.9736A>T	p.Thr3246Ser	missense_variant	Exon 11 of 15	ENST00000375759.8	NP_055816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPEN	ENST00000375759.8 link	c.9736A>T	p.Thr3246Ser	missense_variant	Exon 11 of 15	1	NM_015001.3	ENSP00000364912.3
SPEN	ENST00000704274.1 link	c.5332A>T	p.Thr1778Ser	missense_variant	Exon 1 of 4			ENSP00000515812.1
SPEN	ENST00000438066.2 link	n.*10587A>T		non_coding_transcript_exon_variant	Exon 11 of 15	3		ENSP00000388021.2
SPEN	ENST00000438066.2 link	n.*10587A>T		3_prime_UTR_variant	Exon 11 of 15	3		ENSP00000388021.2

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

55384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000169

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

595198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

298872

African (AFR)

AF:

0.00

AC:

AN:

13946

American (AMR)

AF:

0.00

AC:

AN:

25066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10968

East Asian (EAS)

AF:

0.00

AC:

AN:

17784

South Asian (SAS)

AF:

0.00

AC:

AN:

38712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

442060

Other (OTH)

AF:

0.00

AC:

AN:

24698

GnomAD4 genome

AF:

0.0000181

AC:

AN:

55384

Hom.:

Cov.:

AF XY:

0.0000374

AC XY:

AN XY:

26748

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

14370

American (AMR)

AF:

0.000169

AC:

AN:

5920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1370

East Asian (EAS)

AF:

0.00

AC:

AN:

1564

South Asian (SAS)

AF:

0.00

AC:

AN:

1540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

25332

Other (OTH)

AF:

0.00

AC:

AN:

770

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0060

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.086

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.22

M_CAP

Benign

0.0045

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

PhyloP100

-0.54

PrimateAI

Benign

0.42

PROVEAN

Benign

0.46

REVEL

Benign

0.014

Sift

Benign

0.26

Sift4G

Benign

1.0

Vest4

0.12

ClinPred

0.058

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.033

gMVP

0.041

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over