15-38253162-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_152594.3(SPRED1):c.-24A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000598 in 1,571,726 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: SPRED1 NM_152594.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.157

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000591 (84/1421278) while in subpopulation AMR AF= 0.000509 (20/39322). AF 95% confidence interval is 0.000337. There are 0 homozygotes in gnomad4_exome. There are 50 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.-24A>G		5_prime_UTR_variant	1/7	ENST00000299084.9
SPRED1	XM_005254202.4	c.-24A>G		5_prime_UTR_variant	1/8
SPRED1	XM_047432199.1	c.-187A>G		5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1	c.-151A>G		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.-24A>G		5_prime_UTR_variant	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561205.1	n.315A>G		non_coding_transcript_exon_variant	1/5	5
SPRED1	ENST00000561317.1			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000665 AC: 10 AN: 150342 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 30 AN: 190724 Hom.: 0 AF XY: 0.000138 AC XY: 14 AN XY: 101682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000419

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000588

GnomAD4 exome AF: 0.0000591 AC: 84 AN: 1421278 Hom.: 0 Cov.: 31 AF XY: 0.0000711 AC XY: 50 AN XY: 703096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000509

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000257

Gnomad4 OTH exome AF: 0.0000849

GnomAD4 genome AF: 0.0000665 AC: 10 AN: 150448 Hom.: 0 Cov.: 31 AF XY: 0.0000681 AC XY: 5 AN XY: 73424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000212

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs755230054; hg19: chr15-38545363;