Genetic Variant SPRED1:p.Asn10Asn (chr15-38253215-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_152594.3(SPRED1):c.30C>T(p.Asn10Asn) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000702 in 1,424,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SPRED1
NM_152594.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9800

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.85

Publications

6 publications found

Variant links:

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, Ambry Genetics, Genomics England PanelApp, ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

SPRED1 links:

ENSG00000310144 (HGNC:):

ENSG00000310144 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.30C>T	p.Asn10Asn	splice_region synonymous	Exon 1 of 7	NP_689807.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.30C>T	p.Asn10Asn	splice_region synonymous	Exon 1 of 7	ENSP00000299084.4
SPRED1	ENST00000561317.1	TSL:4	c.-98C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000453680.1
SPRED1	ENST00000561317.1	TSL:4	c.-98C>T		splice_region	Exon 1 of 6	ENSP00000453680.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000521

AC:

AN:

192104

AF XY:

0.00000978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1424606

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32628

American (AMR)

AF:

0.0000249

AC:

AN:

40122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25508

East Asian (EAS)

AF:

0.00

AC:

AN:

37774

South Asian (SAS)

AF:

0.00

AC:

AN:

81300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092008

Other (OTH)

AF:

0.00

AC:

AN:

59006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.9

PromoterAI

0.083

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over