15-38252995-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152594.3(SPRED1):c.-191C>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 0.0012 in 619,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: SPRED1 NM_152594.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20

Genes affected

SPRED1 (HGNC:20249): (sprouty related EVH1 domain containing 1) The protein encoded by this gene is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade. Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-38252995-C-T is Benign according to our data. Variant chr15-38252995-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 315728.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000881 (134/152156) while in subpopulation SAS AF= 0.00145 (7/4816). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.-191C>T		5_prime_UTR_variant	1/7	ENST00000299084.9
SPRED1	XM_005254202.4	c.-191C>T		5_prime_UTR_variant	1/8
SPRED1	XM_047432199.1	c.-354C>T		5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1	c.-318C>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.-191C>T		5_prime_UTR_variant	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561205.1	n.148C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00131 AC: 610 AN: 467288 Hom.: 1 Cov.: 4 AF XY: 0.00138 AC XY: 343 AN XY: 248822

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00229

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00121

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000881 AC: 134 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.000820 AC XY: 61 AN XY: 74388

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000676

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs556907443; hg19: chr15-38545196;