chr15-38253011-G-T

Variant names:

• chr15-38253011-G-T
• rs1312214893
• NM_152594.3:c.-175G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152594.3(SPRED1):​c.-175G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 486,188 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPRED1 NM_152594.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.879
• 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia

ENSG00000310144 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152594.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	NM_152594.3	MANE Select	c.-175G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_689807.1	Q7Z699
	SPRED1	NM_152594.3	MANE Select	c.-175G>T		5_prime_UTR	Exon 1 of 7	NP_689807.1	Q7Z699

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.-175G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.-175G>T		5_prime_UTR	Exon 1 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.-175G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000551439.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 1 AN: 486188 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 259276

⚠️ 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: 13604

American (AMR) AF: 0.00 AC: 0 AN: 24360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15412

East Asian (EAS) AF: 0.00 AC: 0 AN: 31312

South Asian (SAS) AF: 0.00 AC: 0 AN: 51274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2114

European-Non Finnish (NFE) AF: 0.00000345 AC: 1 AN: 289960

Other (OTH) AF: 0.00 AC: 0 AN: 27484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Legius syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		0.88
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1312214893; hg19: chr15-38545212;