1-155257328-G-A

Variant names:

• chr1-155257328-G-A
• rs1430915875
• NM_005698.4:c.736C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005698.4(SCAMP3):​c.736C>T​(p.Leu246Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCAMP3 NM_005698.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.331
• Publications: 0 publications found

Genes affected

SCAMP3 (HGNC:10565): (secretory carrier membrane protein 3) This gene encodes an integral membrane protein that belongs to the secretory carrier membrane protein family. The encoded protein functions as a carrier to the cell surface in post-golgi recycling pathways. This protein is also involved in protein trafficking in endosomal pathways. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]

ENSG00000303088 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042706937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAMP3	NM_005698.4	c.736C>T	p.Leu246Phe	missense_variant	Exon 7 of 9	ENST00000302631.8	NP_005689.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAMP3	ENST00000302631.8	c.736C>T	p.Leu246Phe	missense_variant	Exon 7 of 9	1	NM_005698.4	ENSP00000307275.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736C>T (p.L246F) alteration is located in exon 7 (coding exon 7) of the SCAMP3 gene. This alteration results from a C to T substitution at nucleotide position 736, causing the leucine (L) at amino acid position 246 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.58	N;.
PhyloP100		0.33
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.046
Sift	Benign	0.23	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0020	B;B
Vest4		0.13
MutPred		0.43		Gain of catalytic residue at L246 (P = 0.1466);.;
MVP		0.099
MPC		0.29
ClinPred		0.13	T
GERP RS		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.53
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1430915875; hg19: chr1-155227119;