chr15-38252985-G-A

Variant names:

• chr15-38252985-G-A
• rs770231868
• NM_152594.3:c.-201G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_152594.3(SPRED1):​c.-201G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 605,082 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 0.00061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: SPRED1 NM_152594.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.657
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000611 (93/152152) while in subpopulation NFE AF = 0.00113 (77/67978). AF 95% confidence interval is 0.000929. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 93 AD gene.

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.-201G>A		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.-201G>A		5_prime_UTR	Exon 1 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.-201G>A		5_prime_UTR	Exon 1 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.-201G>A		5_prime_UTR	Exon 1 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000808 AC: 366 AN: 452930 Hom.: 0 Cov.: 3 AF XY: 0.000771 AC XY: 186 AN XY: 241090

African (AFR) AF: 0.000163 AC: 2 AN: 12272

American (AMR) AF: 0.000422 AC: 8 AN: 18956

Ashkenazi Jewish (ASJ) AF: 0.000587 AC: 8 AN: 13634

East Asian (EAS) AF: 0.00 AC: 0 AN: 30996

South Asian (SAS) AF: 0.000601 AC: 28 AN: 46582

European-Finnish (FIN) AF: 0.000239 AC: 7 AN: 29238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1970

European-Non Finnish (NFE) AF: 0.00110 AC: 300 AN: 273306

Other (OTH) AF: 0.000500 AC: 13 AN: 25976

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.000471 AC XY: 35 AN XY: 74368

African (AFR) AF: 0.000217 AC: 9 AN: 41532

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 67978

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000672

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	-0.59
CADD	Benign	18
DANN	Benign	0.95
PhyloP100		0.66
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770231868; hg19: chr15-38545186;