Genetic Variant NM_015001.3:c.70G>A (chr1-15848137-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015001.3(SPEN):c.70G>A(p.Glu24Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,342,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E24D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Publications

0 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 links:

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

SPEN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEN	NM_015001.3	MANE Select	c.70G>A	p.Glu24Lys	missense	Exon 1 of 15	NP_055816.2
	SPEN-AS1	NR_024279.1		n.11C>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPEN	ENST00000375759.8	TSL:1 MANE Select	c.70G>A	p.Glu24Lys	missense	Exon 1 of 15	ENSP00000364912.3	Q96T58
SPEN	ENST00000673875.1		c.-220+11252G>A		intron	N/A	ENSP00000501122.1	A0A669KB49
SPEN-AS1	ENST00000317122.2	TSL:2	n.11C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

163294

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:

0.00000149

AC:

AN:

1342984

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27926

American (AMR)

AF:

0.00

AC:

AN:

33328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22226

East Asian (EAS)

AF:

0.00

AC:

AN:

30640

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5334

European-Non Finnish (NFE)

AF:

9.56e-7

AC:

AN:

1045780

Other (OTH)

AF:

0.00

AC:

AN:

53828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Radio-Tartaglia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

7.7

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.0

REVEL

Benign

0.28

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.37

MutPred

0.45

Gain of MoRF binding (P = 0.0039)

MVP

0.50

MPC

0.93

ClinPred

0.93

GERP RS

3.3

PromoterAI

-0.067

Neutral

(source)

Varity_R

0.41

gMVP

0.80

Mutation Taster

=56/44

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over