1-15935970-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_015001.3(SPEN):c.9730A>G(p.Thr3244Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 758,952 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. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3244P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.451

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023690045).

BP6

Variant 1-15935970-A-G is Benign according to our data. Variant chr1-15935970-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3168965.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000605 (42/693710) while in subpopulation NFE AF = 0.0000771 (39/506080). AF 95% confidence interval is 0.0000577. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEN	NM_015001.3 link	c.9730A>G	p.Thr3244Ala	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.9730A>G	p.Thr3244Ala	missense_variant	Exon 11 of 15	1	NM_015001.3	ENSP00000364912.3
SPEN	ENST00000704274.1 link	c.5326A>G	p.Thr1776Ala	missense_variant	Exon 1 of 4			ENSP00000515812.1
SPEN	ENST00000438066.2 link	n.*10581A>G		non_coding_transcript_exon_variant	Exon 11 of 15	3		ENSP00000388021.2
SPEN	ENST00000438066.2 link	n.*10581A>G		3_prime_UTR_variant	Exon 11 of 15	3		ENSP00000388021.2

Frequencies

GnomAD3 genomes

AF:

0.0000153

AC:

AN:

65242

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:

0.0000329

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

111310

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:

0.0000605

AC:

AN:

693710

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

351402

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

16600

American (AMR)

AF:

0.00

AC:

AN:

28614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13334

East Asian (EAS)

AF:

0.00

AC:

AN:

20288

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1970

European-Non Finnish (NFE)

AF:

0.0000771

AC:

AN:

506080

Other (OTH)

AF:

0.0000350

AC:

AN:

28594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.0000153

AC:

AN:

65242

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

30940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17294

American (AMR)

AF:

0.00

AC:

AN:

6440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1602

East Asian (EAS)

AF:

0.00

AC:

AN:

1984

South Asian (SAS)

AF:

0.00

AC:

AN:

1876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.0000329

AC:

AN:

30374

Other (OTH)

AF:

0.00

AC:

AN:

892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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

ExAC

AF:

0.00000879

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 05, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.35

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.081

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.25

M_CAP

Benign

0.0027

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.45

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.12

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

0.92

Vest4

0.045

ClinPred

0.017

GERP RS

-0.36

Varity_R

0.025

gMVP

0.079

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over