rs376134678

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152594.3(SPRED1):c.377-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,599,000 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

SPRED1
NM_152594.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004655

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.105

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 15-38324753-A-G is Benign according to our data. Variant chr15-38324753-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 47968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38324753-A-G is described in Lovd as [Benign]. Variant chr15-38324753-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00023 (35/152254) while in subpopulation AFR AF= 0.000794 (33/41566). AF 95% confidence interval is 0.00058. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3 linkuse as main transcript	c.377-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
SPRED1	ENST00000299084.9 linkuse as main transcript	c.377-10A>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_152594.3	P1
SPRED1	ENST00000561317.1 linkuse as main transcript	c.314-10A>G	splice_polypyrimidine_tract_variant, intron_variant	4
SPRED1	ENST00000561205.1 linkuse as main transcript	n.715-10A>G	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

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:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000432

AC:

AN:

231320

Hom.:

AF XY:

0.0000641

AC XY:

AN XY:

124824

show subpopulations

Gnomad AFR exome

AF:

0.000563

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1446746

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

718462

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

Gnomad4 AMR exome

AF:

0.0000462

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000906

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.000230

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000287

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2013	377-10A>G in intron 3 of SPRED1: This variant has been identified by our labora tory in a proband and an unaffected parent. This variant is located in the 3' sp lice acceptor region but does not affect the invariant -1 and -2 positions. In a ddition, computational tools do not predict altered splicing. This variant has b een identified in 0.05% (2/4392) of African American chromosomes from a large po pulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). In addition, the adenine nucleotide is not conserved across evolutionary dis tinct species at position 377-10, and several mammals have a guanine at this pos ition. Therefore, the 377-10A>G variant is likely to be benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

- -

Legius syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

Cadd

Benign

1.7

Dann

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over