NM_152594.3:c.583-7A>G

Variant names:

• chr15-38349415-A-G
• rs115970207
• NM_152594.3:c.583-7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152594.3(SPRED1):​c.583-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,601,084 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: SPRED1 NM_152594.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003110
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.12
• Publications: 1 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-38349415-A-G is Benign according to our data. Variant chr15-38349415-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00601 (915/152264) while in subpopulation AFR AF = 0.0205 (853/41558). AF 95% confidence interval is 0.0194. There are 9 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 915 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.583-7A>G		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.583-7A>G		splice_region intron	N/A	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.619-7A>G		splice_region intron	N/A	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.604-7A>G		splice_region intron	N/A	ENSP00000621998.1

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 912 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00166 AC: 415 AN: 250670 AF XY: 0.00116

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000638 AC: 925 AN: 1448820 Hom.: 4 Cov.: 28 AF XY: 0.000527 AC XY: 380 AN XY: 721614

African (AFR) AF: 0.0204 AC: 676 AN: 33200

American (AMR) AF: 0.00180 AC: 80 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.0000763 AC: 84 AN: 1100692

Other (OTH) AF: 0.00137 AC: 82 AN: 59892

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74438

African (AFR) AF: 0.0205 AC: 853 AN: 41558

American (AMR) AF: 0.00281 AC: 43 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67994

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00292 Hom.: 3

Bravo AF: 0.00689

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Legius syndrome (4)
-	-	4	not specified (4)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not provided (1)
-	-	1	SPRED1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.0
DANN	Benign	0.83
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs115970207; hg19: chr15-38641616;