chr15-38253186-A-T

Position:

• chr15-38253186-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_152594.3(SPRED1):​c.1A>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPRED1 NM_152594.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.46

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152594.3 (SPRED1) was described as [Likely_pathogenic] in ClinVar as 930640
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38253186-A-T is Pathogenic according to our data. Variant chr15-38253186-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3362511.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.1A>T	p.Met1?	start_lost	1/7	ENST00000299084.9
SPRED1	XM_005254202.4	c.1A>T	p.Met1?	start_lost	1/8
SPRED1	XM_047432199.1	c.-163A>T		5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1	c.-127A>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.1A>T	p.Met1?	start_lost	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.-127A>T		5_prime_UTR_variant	1/6	4
SPRED1	ENST00000561205.1	n.339A>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.096
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.044	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.17	B
Vest4		0.92
MutPred		1.0		Loss of phosphorylation at T5 (P = 0.2003);
MVP		0.98
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-38545387;