rs1048605006

Variant names:

• chr15-38252891-CCT-C
• rs1048605006
• NM_152594.3:c.-290_-289delCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_152594.3(SPRED1):​c.-290_-289delCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000576 in 520,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPRED1 NM_152594.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.402
• Publications: 0 publications found

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]

SPRED1 Gene-Disease associations (from GenCC):

• Legius syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000310144 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 15-38252891-CCT-C is Benign according to our data. Variant chr15-38252891-CCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 631554.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.-290_-289delCT		5_prime_UTR_variant	Exon 1 of 7	ENST00000299084.9	NP_689807.1
SPRED1	XM_005254202.4	c.-290_-289delCT		5_prime_UTR_variant	Exon 1 of 8		XP_005254259.1
SPRED1	XM_047432199.1	c.-453_-452delCT		5_prime_UTR_variant	Exon 1 of 9		XP_047288155.1
SPRED1	XM_047432200.1	c.-417_-416delCT		5_prime_UTR_variant	Exon 1 of 8		XP_047288156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.-290_-289delCT		5_prime_UTR_variant	Exon 1 of 7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561205.1	n.49_50delCT		non_coding_transcript_exon_variant	Exon 1 of 5	5
ENSG00000310144	ENST00000847565.1	n.95+674_95+675delAG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 AF: 0.00000271 AC: 1 AN: 368596 Hom.: 0 AF XY: 0.00000511 AC XY: 1 AN XY: 195656

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

African (AFR) AF: 0.00 AC: 0 AN: 9964

American (AMR) AF: 0.00 AC: 0 AN: 15906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10982

East Asian (EAS) AF: 0.00 AC: 0 AN: 23892

South Asian (SAS) AF: 0.00 AC: 0 AN: 43688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1580

European-Non Finnish (NFE) AF: 0.00000456 AC: 1 AN: 219338

Other (OTH) AF: 0.00 AC: 0 AN: 21096

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Benign:1

May 23, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Patient has a pathogenic variant in NF1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40

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: rs1048605006; hg19: chr15-38545092;