chr15-75018813-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_138967.4(SCAMP5):​c.538G>T​(p.Gly180Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

SCAMP5
NM_138967.4 missense

Scores

13
3
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 9.61
Variant links:
Genes affected
SCAMP5 (HGNC:30386): (secretory carrier membrane protein 5) Involved in positive regulation of cytokine production; regulation of vesicle-mediated transport; and response to endoplasmic reticulum stress. Located in Golgi apparatus; plasma membrane; and recycling endosome membrane. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.796
PP5
Variant 15-75018813-G-T is Pathogenic according to our data. Variant chr15-75018813-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 872248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCAMP5NM_138967.4 linkuse as main transcriptc.538G>T p.Gly180Trp missense_variant 7/7 ENST00000425597.8 NP_620417.1 Q8TAC9-1A0A0A8K8F5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCAMP5ENST00000425597.8 linkuse as main transcriptc.538G>T p.Gly180Trp missense_variant 7/71 NM_138967.4 ENSP00000406547.3 Q8TAC9-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 09, 2022Published functional studies using Drosophila fly models showed reduced protein levels and suggested a dominant-negative effect (Hubert et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33663553, 33390987, 31439720) -
Uncertain significance, no assertion criteria providedliterature onlyOMIMNov 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2019- -
Global developmental delay Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing3billionOct 25, 2021The variant has been previously reported as de novo insimilarly affected unrelated individual (PMID:31439720, PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.649, 3Cnet: 0.848, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Macrocephaly-developmental delay syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenNov 30, 2023- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 04, 2021The c.538G>T (p.G180W) alteration is located in exon 8 (coding exon 6) of the SCAMP5 gene. This alteration results from a G to T substitution at nucleotide position 538, causing the glycine (G) at amino acid position 180 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated patients with seizures, developmental delay, intellectual disability, and abnormal neurological exam findings. Some patients were also reported to have autism spectrum disorder and/or dysmorphic facial features (Hubert, 2020; Jiao 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.G180W alteration decreased protein levels compared to wild type protein when expressed in the Drosophila fat body using the corresponding alteration, p.G302W, in the fly homolog. Additionally, expression of the p.G302W alteration in Drosophila showed abnormal eye formation and disturbed the normal fly neurological phenotype (Hubert, 2020). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
SCAMP5-related neurodevelopmental disorder with autistic features and seizures Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 01, 2023The SCAMP5 c.538G>T (p.Gly180Trp) missense variant has been reported in a de novo state in six unrelated individuals with developmental delay, seizures, motor disorders, behavioral differences, and abnormalities on brain MRI (PMID: 31439720; 33390987). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies of this variant conducted in a Drosophila knock-in model suggest it has a dominant-negative effect (PMID: 31439720). This variant has been classified as pathogenic or likely pathogenic by four submitters in ClinVar. Based on the available evidence, the c.538G>T (p.Gly180Trp) variant is classified as likely pathogenic for SCAMP5-related neurodevelopmental disorder with autistic features and seizures. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;.;D;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D;D
M_CAP
Benign
0.061
D
MetaRNN
Pathogenic
0.80
D;D;D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Pathogenic
3.4
M;.;M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-7.3
D;D;D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.74
MutPred
0.61
Gain of solvent accessibility (P = 0.001);.;Gain of solvent accessibility (P = 0.001);.;
MVP
0.63
MPC
1.9
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.95
gMVP
0.98

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

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

Other links and lift over

dbSNP: rs1184981709; hg19: chr15-75311154; API