1-15876264-C-T

Position:

chr1-15876264-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_015001.3(SPEN):c.467C>T(p.Thr156Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPEN. . Gene score misZ 2.8932 (greater than the threshold 3.09). Trascript score misZ 5.0985 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, Radio-Tartaglia syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.24243042).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000239 (35/1461868) while in subpopulation SAS AF= 0.000151 (13/86252). AF 95% confidence interval is 0.0000889. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEN	NM_015001.3 linkuse as main transcript	c.467C>T	p.Thr156Met	missense_variant	3/15	ENST00000375759.8	NP_055816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SPEN	ENST00000375759.8 linkuse as main transcript	c.467C>T	p.Thr156Met	missense_variant	3/15	1	NM_015001.3	ENSP00000364912	P1
SPEN	ENST00000673875.1 linkuse as main transcript	c.263C>T	p.Thr88Met	missense_variant	4/12			ENSP00000501122
SPEN	ENST00000471538.1 linkuse as main transcript	n.957C>T		non_coding_transcript_exon_variant	2/2	2
SPEN	ENST00000438066.2 linkuse as main transcript	c.*1318C>T		3_prime_UTR_variant, NMD_transcript_variant	3/15	3		ENSP00000388021

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251410

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.467C>T (p.T156M) alteration is located in exon 3 (coding exon 3) of the SPEN gene. This alteration results from a C to T substitution at nucleotide position 467, causing the threonine (T) at amino acid position 156 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.020

D;T

Polyphen

1.0

D;.

Vest4

0.61

MVP

0.41

MPC

1.8

ClinPred

0.35

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.094

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over