1-15935976-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_015001.3(SPEN):c.9736A>G(p.Thr3246Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 650,580 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000036 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000071 ( 0 hom. )

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02224642).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000706 (42/595192) while in subpopulation NFE AF = 0.0000882 (39/442058). AF 95% confidence interval is 0.000066. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015001.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEN	NM_015001.3	MANE Select	c.9736A>G	p.Thr3246Ala	missense	Exon 11 of 15	NP_055816.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPEN	ENST00000375759.8	TSL:1 MANE Select	c.9736A>G	p.Thr3246Ala	missense	Exon 11 of 15	ENSP00000364912.3
SPEN	ENST00000704274.1		c.5332A>G	p.Thr1778Ala	missense	Exon 1 of 4	ENSP00000515812.1
SPEN	ENST00000438066.2	TSL:3	n.*10587A>G		non_coding_transcript_exon	Exon 11 of 15	ENSP00000388021.2

Frequencies

GnomAD3 genomes

AF:

0.0000361

AC:

AN:

55388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000789

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

81104

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

AN:

595192

Hom.:

Cov.:

AF XY:

0.0000535

AC XY:

AN XY:

298870

show subpopulations

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:

0.0000562

AC:

AN:

17784

South Asian (SAS)

AF:

0.0000258

AC:

AN:

38710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1688

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

442058

Other (OTH)

AF:

0.0000405

AC:

AN:

24696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000361

AC:

AN:

55388

Hom.:

Cov.:

AF XY:

0.0000748

AC XY:

AN XY:

26752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14370

American (AMR)

AF:

0.00

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:

4152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000789

AC:

AN:

25334

Other (OTH)

AF:

0.00

AC:

AN:

770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000864

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0070

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.10

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.24

M_CAP

Benign

0.0050

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

PhyloP100

-0.54

PrimateAI

Benign

0.43

PROVEAN

Benign

0.14

REVEL

Benign

0.015

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.042

MutPred

0.20

Loss of glycosylation at T3246 (P = 1e-04)

MVP

0.043

MPC

0.23

ClinPred

0.019

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.022

gMVP

0.072

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over