NM_015001.3:c.9737C>G

Variant names:

• chr1-15935977-C-G
• NM_015001.3:c.9737C>G
• SPEN p.Thr3246Ser

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015001.3(SPEN):​c.9737C>G​(p.Thr3246Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 24)
• Consequence: SPEN NM_015001.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 0 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03300628).

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.9737C>G	p.Thr3246Ser	missense	Exon 11 of 15	NP_055816.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEN	ENST00000375759.8	TSL:1 MANE Select	c.9737C>G	p.Thr3246Ser	missense	Exon 11 of 15	ENSP00000364912.3	Q96T58
	SPEN	ENST00000704274.1		c.5333C>G	p.Thr1778Ser	missense	Exon 1 of 4	ENSP00000515812.1	A0A994J7B7
	SPEN	ENST00000438066.2	TSL:3	n.*10588C>G		non_coding_transcript_exon	Exon 11 of 15	ENSP00000388021.2	F6WRY4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.020
DANN	Benign	0.15
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.068
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.025
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.035
gMVP		0.041
Mutation Taster		=95/5	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-16262472;