chr7-138627446-A-G

Position:

• chr7-138627446-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001139456.2(SVOPL):​c.1085T>C​(p.Ile362Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SVOPL NM_001139456.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42

Genes affected

SVOPL (HGNC:27034): (SVOP like) The protein encoded by this gene is thought to be a member of solute carrier family 22, which includes transmembrane proteins that transport toxins and drugs from the body. This gene is a paralog of the SVOP gene that encodes synaptic vesicle 2-related protein. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SVOPL	NM_001139456.2	c.1085T>C	p.Ile362Thr	missense_variant	12/16	ENST00000674285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SVOPL	ENST00000674285.1	c.1085T>C	p.Ile362Thr	missense_variant	12/16		NM_001139456.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.1085T>C (p.I362T) alteration is located in exon 11 (coding exon 11) of the SVOPL gene. This alteration results from a T to C substitution at nucleotide position 1085, causing the isoleucine (I) at amino acid position 362 to be replaced by a threonine (T). 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.81
MutPred		0.64		.;.;.;Loss of stability (P = 0.0235);
MVP		0.66
MPC		0.065
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.90

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: rs773196860; hg19: chr7-138312191;