1-15935976-A-T

Variant names:

• chr1-15935976-A-T
• rs769360962
• NM_015001.3:c.9736A>T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543

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]

ACMG classification

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	c.9736A>T	p.Thr3246Ser	missense_variant	Exon 11 of 15	ENST00000375759.8	NP_055816.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 1 AN: 55384 Hom.: 0 Cov.: 0

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: 0 AN: 595198 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 1 AN: 55384 Hom.: 0 Cov.: 0 AF XY: 0.0000374 AC XY: 1 AN XY: 26748

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	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0060
DANN	Benign	0.15
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.014
Sift	Benign	0.26	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.20		Loss of glycosylation at P3245 (P = 0.1603);
MVP		0.043
MPC		0.21
ClinPred		0.058	T
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

Other links and lift over

dbSNP: rs769360962; hg19: chr1-16262471;