rs750686148

chr15-38299522-G-Achr15-38299522-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_152594.3(SPRED1):c.182G>A(p.Arg61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10710737).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.182G>A	p.Arg61His	missense_variant	2/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.182G>A	p.Arg61His	missense_variant	2/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.119G>A	p.Arg40His	missense_variant	3/6	4
SPRED1	ENST00000561205.1	n.520G>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251124 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135722

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 14, 2023

Variant summary: SPRED1 c.182G>A (p.Arg61His) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251124 control chromosomes (i.e., 5 heterozygotes; gnomAD v2.1 Exomes dataset). Although the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, the allele frequency in controls is not suggestive of highly penetrant variant responsible for autosomal dominant disease. c.182G>A has been reported in the literature in individuals affected psoriasis, including one de novo occurrence (e.g., Li_JAutoimmun_2020 and Li_JDermatol_2020). Additionally, the variant was identified in an individual with Noonan syndrome, however authors classified this variant as likely benign due to a co-occurring pathogenic PTPN11 variant (Lodi_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). Co-occurrences with other pathogenic variants have been observed (PTPN11 c.922A>G, p.Asn308Asp, Lodi_2020; PTPN11 c.1510A>G, p.Met504Val, Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31629629, 32396270, 32806529). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 61 of the SPRED1 protein (p.Arg61His). This variant is present in population databases (rs750686148, gnomAD 0.008%). This missense change has been observed in individual(s) with psoriasis (PMID: 31629629). ClinVar contains an entry for this variant (Variation ID: 468794). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SPRED1 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Benign	0.84
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.44	N;.
MutationTaster	Benign	0.73	D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	2.8	N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.010	B;.
Vest4		0.16
MutPred		0.57		Gain of sheet (P = 0.0827);.;
MVP		0.61
MPC		0.42
ClinPred		0.080	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs750686148; hg19: chr15-38591723; COSMIC: COSV54437164;