chr1-15848067-C-T

Position:

• chr1-15848067-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_015001.3(SPEN):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,453,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SPEN NM_015001.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.440

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-AS1 (HGNC:55937): (SPEN antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-15848067-C-T is Benign according to our data. Variant chr1-15848067-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3047959.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000172 (26/151408) while in subpopulation NFE AF= 0.000325 (22/67796). AF 95% confidence interval is 0.000219. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEN	NM_015001.3	c.-1C>T		5_prime_UTR_variant	1/15	ENST00000375759.8	NP_055816.2
SPEN-AS1	NR_024279.1	n.40+41G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEN	ENST00000375759.8	c.-1C>T		5_prime_UTR_variant	1/15	1	NM_015001.3	ENSP00000364912	P1
SPEN-AS1	ENST00000317122.2	n.40+41G>A		intron_variant, non_coding_transcript_variant		2
SPEN	ENST00000673875.1	c.-220+11182C>T		intron_variant				ENSP00000501122
SPEN	ENST00000438066.2	c.-1C>T		5_prime_UTR_variant, NMD_transcript_variant	1/15	3		ENSP00000388021

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 26 AN: 151408 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000325

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 20 AN: 137964 Hom.: 0 AF XY: 0.000106 AC XY: 8 AN XY: 75484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000611

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000291 AC: 379 AN: 1302190 Hom.: 0 Cov.: 30 AF XY: 0.000278 AC XY: 179 AN XY: 644640

Gnomad4 AFR exome AF: 0.000109

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000144

Gnomad4 FIN exome AF: 0.000129

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000193

GnomAD4 genome AF: 0.000172 AC: 26 AN: 151408 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 73940

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000195

Gnomad4 NFE AF: 0.000325

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000465 Hom.: 0

Bravo AF: 0.000185

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SPEN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs144566113; hg19: chr1-16174562;