rs7180446

Variant names:

• chr15-38339729-C-A
• rs7180446
• NM_152594.3:c.424-8C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-38339729-C-A
• chr15-38339729-C-G
• chr15-38339729-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152594.3(SPRED1):​c.424-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,612,586 control chromosomes in the GnomAD database, including 629,837 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (52403 hom., cov: 30)
  • Exomes 𝑓: 0.89 (577434 hom.)
• Consequence: SPRED1 NM_152594.3 splice_region, intron
• Scores: Splicing: ADA: 0.005107
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.863
• Publications: 16 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, PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-38339729-C-A is Benign according to our data. Variant chr15-38339729-C-A is described in ClinVar as Benign. ClinVar VariationId is 41453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

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.424-8C>A		splice_region intron	N/A	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.424-8C>A		splice_region intron	N/A	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.460-8C>A		splice_region intron	N/A	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.445-8C>A		splice_region intron	N/A	ENSP00000621998.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125209 AN: 151918 Hom.: 52390 Cov.: 30

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.879

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.897

Gnomad OTH AF: 0.829

GnomAD2 exomes AF: 0.865 AC: 217263 AN: 251082 AF XY: 0.873

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.909

Gnomad EAS exome AF: 0.789

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.896

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.888 AC: 1296882 AN: 1460550 Hom.: 577434 Cov.: 42 AF XY: 0.889 AC XY: 645933 AN XY: 726618

African (AFR) AF: 0.646 AC: 21576 AN: 33398

American (AMR) AF: 0.832 AC: 37194 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23677 AN: 26110

East Asian (EAS) AF: 0.784 AC: 31063 AN: 39638

South Asian (SAS) AF: 0.892 AC: 76930 AN: 86226

European-Finnish (FIN) AF: 0.933 AC: 49763 AN: 53348

Middle Eastern (MID) AF: 0.840 AC: 4838 AN: 5758

European-Non Finnish (NFE) AF: 0.899 AC: 999047 AN: 1111028

Other (OTH) AF: 0.875 AC: 52794 AN: 60346

GnomAD4 genome AF: 0.824 AC: 125273 AN: 152036 Hom.: 52403 Cov.: 30 AF XY: 0.826 AC XY: 61370 AN XY: 74316

African (AFR) AF: 0.663 AC: 27488 AN: 41444

American (AMR) AF: 0.842 AC: 12845 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3129 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4090 AN: 5164

South Asian (SAS) AF: 0.879 AC: 4229 AN: 4812

European-Finnish (FIN) AF: 0.934 AC: 9888 AN: 10588

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.897 AC: 60940 AN: 67974

Other (OTH) AF: 0.822 AC: 1738 AN: 2114

Alfa AF: 0.872 Hom.: 114544

Bravo AF: 0.805

Asia WGS AF: 0.794 AC: 2764 AN: 3478

EpiCase AF: 0.889

EpiControl AF: 0.886

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Legius syndrome (6)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.9
DANN	Benign	0.67
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.082
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7180446;

hg19: chr15-38631930;

COSMIC: COSV54434951;