rs150922162

Variant names:

• chr1-15872825-C-T
• rs150922162
• NM_015001.3:c.93C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015001.3(SPEN):​c.93C>T​(p.Arg31Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,492,066 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: SPEN NM_015001.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.16
• Publications: 1 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-15872825-C-T is Benign according to our data. Variant chr1-15872825-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3038799.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00163 (248/152186) while in subpopulation NFE AF = 0.00273 (186/68014). AF 95% confidence interval is 0.00241. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 248 AD gene.

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.93C>T	p.Arg31Arg	synonymous	Exon 2 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.93C>T	p.Arg31Arg	synonymous	Exon 2 of 15	ENSP00000364912.3	Q96T58
	SPEN	ENST00000673875.1		c.-112C>T		5_prime_UTR	Exon 3 of 12	ENSP00000501122.1	A0A669KB49
	SPEN	ENST00000438066.2	TSL:3	n.93C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000388021.2	F6WRY4

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00148 AC: 283 AN: 191196 AF XY: 0.00160

Gnomad AFR exome AF: 0.000778

Gnomad AMR exome AF: 0.000895

Gnomad ASJ exome AF: 0.000649

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000168

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00391 AC: 5233 AN: 1339880 Hom.: 15 Cov.: 31 AF XY: 0.00379 AC XY: 2481 AN XY: 654330

African (AFR) AF: 0.000660 AC: 20 AN: 30324

American (AMR) AF: 0.00107 AC: 33 AN: 30892

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 13 AN: 19968

East Asian (EAS) AF: 0.00 AC: 0 AN: 38366

South Asian (SAS) AF: 0.0000153 AC: 1 AN: 65254

European-Finnish (FIN) AF: 0.000183 AC: 9 AN: 49188

Middle Eastern (MID) AF: 0.000193 AC: 1 AN: 5190

European-Non Finnish (NFE) AF: 0.00474 AC: 4959 AN: 1045772

Other (OTH) AF: 0.00359 AC: 197 AN: 54926

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152186 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74382

African (AFR) AF: 0.000674 AC: 28 AN: 41526

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68014

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.00180

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	SPEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.57
DANN	Benign	0.53
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=93/7	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

Other links and lift over

dbSNP: rs150922162; hg19: chr1-16199320; COSMIC: COSV65364696; COSMIC: COSV65364696;