15-75018813-G-T

Variant names:

• chr15-75018813-G-T
• rs1184981709
• NM_138967.4:c.538G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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. 13/22 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 9.61
• Publications: 2 publications found

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]

SCAMP5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina
• epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 872248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAMP5	NM_138967.4	c.538G>T	p.Gly180Trp	missense_variant	Exon 7 of 7	ENST00000425597.8	NP_620417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAMP5	ENST00000425597.8	c.538G>T	p.Gly180Trp	missense_variant	Exon 7 of 7	1	NM_138967.4	ENSP00000406547.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Nov 10, 2020

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published 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) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Global developmental delay Pathogenic:1

Oct 25, 2021

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Nov 30, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Oct 04, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Jun 01, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

SCAMP5-related neurodevelopmental and movement disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 01-17-2023 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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;.
PhyloP100		9.6
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1184981709; hg19: chr15-75311154;