15-75018813-G-T

Position:

• chr15-75018813-G-T

Variant summary

Our verdict is Pathogenic. Variant got 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. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 9.61

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 (HGNC:):

ACMG classification

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
SCAMP5	NM_138967.4	c.538G>T	p.Gly180Trp	missense_variant	7/7	ENST00000425597.8	NP_620417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCAMP5	ENST00000425597.8	c.538G>T	p.Gly180Trp	missense_variant	7/7	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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	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) -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -

Global developmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 25, 2021

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Nov 30, 2023

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2021

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 01, 2023

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. -

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

Other links and lift over

dbSNP: rs1184981709; hg19: chr15-75311154;