1-15872832-A-G

Position:

• chr1-15872832-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_015001.3(SPEN):​c.100A>G​(p.Ser34Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,343,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SPEN NM_015001.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPEN. . Gene score misZ 2.8932 (greater than the threshold 3.09). Trascript score misZ 5.0985 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, Radio-Tartaglia syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEN	NM_015001.3	c.100A>G	p.Ser34Gly	missense_variant	2/15	ENST00000375759.8	NP_055816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEN	ENST00000375759.8	c.100A>G	p.Ser34Gly	missense_variant	2/15	1	NM_015001.3	ENSP00000364912	P1
SPEN	ENST00000673875.1	c.-105A>G		5_prime_UTR_variant	3/12			ENSP00000501122
SPEN	ENST00000438066.2	c.100A>G	p.Ser34Gly	missense_variant, NMD_transcript_variant	2/15	3		ENSP00000388021

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343500 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 656728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000321

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: 0.0000182

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.55		Loss of phosphorylation at S34 (P = 0.019);
MVP		0.43
MPC		1.7
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.71

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: rs2070595255; hg19: chr1-16199327;