chr1-15848139-G-C

Position:

chr1-15848139-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_015001.3(SPEN):c.72G>C(p.Glu24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,494,110 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E24K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

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:

SPEN-AS1 (HGNC:55937): (SPEN antisense RNA 1)

SPEN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.35963455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEN	NM_015001.3 linkuse as main transcript	c.72G>C	p.Glu24Asp	missense_variant	1/15	ENST00000375759.8
SPEN-AS1	NR_024279.1 linkuse as main transcript	n.9C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPEN	ENST00000375759.8 linkuse as main transcript	c.72G>C	p.Glu24Asp	missense_variant	1/15	1	NM_015001.3	P1
SPEN-AS1	ENST00000317122.2 linkuse as main transcript	n.9C>G		non_coding_transcript_exon_variant	1/2	2
SPEN	ENST00000673875.1 linkuse as main transcript	c.-220+11254G>C		intron_variant
SPEN	ENST00000438066.2 linkuse as main transcript	c.72G>C	p.Glu24Asp	missense_variant, NMD_transcript_variant	1/15	3

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151140

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:

0.000193

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

AF:

7.45e-7

AC:

AN:

1342970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

666100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000186

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151140

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73786

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SPEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 24 of the SPEN protein (p.Glu24Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.36

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

REVEL

Benign

0.12

Sift

Benign

0.051

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.25

MutPred

0.40

Gain of MoRF binding (P = 0.1112);

MVP

0.49

MPC

0.76

ClinPred

0.61

GERP RS

3.3

Varity_R

0.28

gMVP

0.67

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