Genetic Variant NM_015001.3:c.9736A>T (chr1-15935976-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015001.3(SPEN):c.9736A>T(p.Thr3246Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000018 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPEN
NM_015001.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.543

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02856204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEN	NM_015001.3 link	c.9736A>T	p.Thr3246Ser	missense_variant	Exon 11 of 15	ENST00000375759.8	NP_055816.2	Q96T58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPEN	ENST00000375759.8 link	c.9736A>T	p.Thr3246Ser	missense_variant	Exon 11 of 15	1	NM_015001.3	ENSP00000364912.3	Q96T58
SPEN	ENST00000704274.1 link	c.5332A>T	p.Thr1778Ser	missense_variant	Exon 1 of 4			ENSP00000515812.1	A0A994J7B7
SPEN	ENST00000438066.2 link	n.*10587A>T		non_coding_transcript_exon_variant	Exon 11 of 15	3		ENSP00000388021.2	F6WRY4
SPEN	ENST00000438066.2 link	n.*10587A>T		3_prime_UTR_variant	Exon 11 of 15	3		ENSP00000388021.2	F6WRY4

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

55384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

595198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

298872

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:

0.00

GnomAD4 genome

AF:

0.0000181

AC:

AN:

55384

Hom.:

Cov.:

AF XY:

0.0000374

AC XY:

AN XY:

26748

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000169

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0060

DANN

Benign

0.15

DEOGEN2

Benign

0.086

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.22

M_CAP

Benign

0.0045

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

PrimateAI

Benign

0.42

PROVEAN

Benign

0.46

REVEL

Benign

0.014

Sift

Benign

0.26

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.12

MutPred

0.20

Loss of glycosylation at P3245 (P = 0.1603);

MVP

0.043

MPC

0.21

ClinPred

0.058

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.033

gMVP

0.041

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over