chr1-15935976-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 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: 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
• Publications: 10 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02856204).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEN	NM_015001.3	MANE Select	c.9736A>T	p.Thr3246Ser	missense	Exon 11 of 15	NP_055816.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEN	ENST00000375759.8	TSL:1 MANE Select	c.9736A>T	p.Thr3246Ser	missense	Exon 11 of 15	ENSP00000364912.3
	SPEN	ENST00000704274.1		c.5332A>T	p.Thr1778Ser	missense	Exon 1 of 4	ENSP00000515812.1
	SPEN	ENST00000438066.2	TSL:3	n.*10587A>T		non_coding_transcript_exon	Exon 11 of 15	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

African (AFR) AF: 0.00 AC: 0 AN: 13946

American (AMR) AF: 0.00 AC: 0 AN: 25066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10968

East Asian (EAS) AF: 0.00 AC: 0 AN: 17784

South Asian (SAS) AF: 0.00 AC: 0 AN: 38712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 442060

Other (OTH) AF: 0.00 AC: 0 AN: 24698

GnomAD4 genome AF: 0.0000181 AC: 1 AN: 55384 Hom.: 0 Cov.: 0 AF XY: 0.0000374 AC XY: 1 AN XY: 26748

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14370

American (AMR) AF: 0.000169 AC: 1 AN: 5920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1370

East Asian (EAS) AF: 0.00 AC: 0 AN: 1564

South Asian (SAS) AF: 0.00 AC: 0 AN: 1540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 25332

Other (OTH) AF: 0.00 AC: 0 AN: 770

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.54
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
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

Other links and lift over

dbSNP: rs769360962; hg19: chr1-16262471;