rs369711772

Variant names:

• chr15-38351292-G-A
• rs369711772
• NM_152594.3:c.963G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-38351292-G-A
• chr15-38351292-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_152594.3(SPRED1):​c.963G>A​(p.Lys321Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,980 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SPRED1 NM_152594.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.94
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-38351292-G-A is Benign according to our data. Variant chr15-38351292-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 315737.
• BP7: Synonymous conserved (PhyloP=2.94 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000208 (304/1461812) while in subpopulation NFE AF = 0.000257 (286/1111992). AF 95% confidence interval is 0.000232. There are 0 homozygotes in GnomAdExome4. There are 147 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 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.963G>A	p.Lys321Lys	synonymous	Exon 7 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.963G>A	p.Lys321Lys	synonymous	Exon 7 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.999G>A	p.Lys333Lys	synonymous	Exon 8 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.984G>A	p.Lys328Lys	synonymous	Exon 8 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251024 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 147 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000257 AC: 286 AN: 1111992

Other (OTH) AF: 0.000265 AC: 16 AN: 60390

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000947 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Legius syndrome (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.4
DANN	Benign	0.60
PhyloP100		2.9

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: rs369711772; hg19: chr15-38643493;