chr15-38349514-C-T

Variant names:

• chr15-38349514-C-T
• rs144764225
• NM_152594.3:c.675C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152594.3(SPRED1):​c.675C>T​(p.Ser225Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,606,344 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S225S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: SPRED1 NM_152594.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.504
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-38349514-C-T is Benign according to our data. Variant chr15-38349514-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.504 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000756 (115/152020) while in subpopulation SAS AF = 0.00166 (8/4808). AF 95% confidence interval is 0.000827. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 115 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.675C>T	p.Ser225Ser	synonymous	Exon 6 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.675C>T	p.Ser225Ser	synonymous	Exon 6 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.711C>T	p.Ser237Ser	synonymous	Exon 7 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.696C>T	p.Ser232Ser	synonymous	Exon 7 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes AF: 0.000757 AC: 115 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00105 AC: 262 AN: 249546 AF XY: 0.00116

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.00111 AC: 1615 AN: 1454324 Hom.: 2 Cov.: 28 AF XY: 0.00112 AC XY: 812 AN XY: 723884

African (AFR) AF: 0.000210 AC: 7 AN: 33320

American (AMR) AF: 0.00144 AC: 64 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.000960 AC: 25 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00119 AC: 102 AN: 86074

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53306

Middle Eastern (MID) AF: 0.00870 AC: 50 AN: 5746

European-Non Finnish (NFE) AF: 0.00116 AC: 1288 AN: 1105648

Other (OTH) AF: 0.00123 AC: 74 AN: 60066

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.000781 AC XY: 58 AN XY: 74282

African (AFR) AF: 0.000362 AC: 15 AN: 41470

American (AMR) AF: 0.00111 AC: 17 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4808

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67972

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000808 Hom.: 0

Bravo AF: 0.000854

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Legius syndrome (4)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	SPRED1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.7
DANN	Benign	0.87
PhyloP100		0.50
Mutation Taster		=99/1	polymorphism

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: rs144764225; hg19: chr15-38641715; COSMIC: COSV100136142;