rs13850

Positions:

• chr15-32641754-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144757.3(SCG5):​c.-32A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 152,322 control chromosomes in the GnomAD database, including 1,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1119 hom., cov: 32)
  • Exomes 𝑓: 0.21 (3 hom.)
• Consequence: SCG5 NM_001144757.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.55

Genes affected

SCG5 (HGNC:10816): (secretogranin V) This gene encodes a secreted chaperone protein that prevents the aggregation of other secreted proteins, including proteins that are associated with neurodegenerative and metabolic disease. The encoded protein may be best known for its role in the trafficking and activation of prohormone convertase PC2 (encoded by Gene ID: 5126). Phosphorylation of the encoded protein has been shown to have an inhibitory effect on its chaperone function. This gene also produces a ARHGAP11A-SCG5 readthrough transcript and ARHGAP11A-SCG5 protein. [provided by RefSeq, Feb 2019]

ARHGAP11A-SCG5 (HGNC:56310): (ARHGAP11A-SCG5 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ARHGAP11A (Rho GTPase activating protein 11A) and SCG5 (secretogranin V) genes on chromosome 15q13.3. The readthrough transcript encodes a fusion protein that shares sequence identity with both the ARHGAP11A and SCG5 gene products. [provided by RefSeq, Feb 2019]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-32641754-A-T is Benign according to our data. Variant chr15-32641754-A-T is described in ClinVar as [Benign]. Clinvar id is 1287486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCG5	NM_001144757.3	c.-32A>T		5_prime_UTR_premature_start_codon_gain_variant	1/6	ENST00000300175.9	NP_001138229.1
SCG5	NM_001144757.3	c.-32A>T		5_prime_UTR_variant	1/6	ENST00000300175.9	NP_001138229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCG5	ENST00000300175.9	c.-32A>T		5_prime_UTR_premature_start_codon_gain_variant	1/6	1	NM_001144757.3	ENSP00000300175.4
SCG5	ENST00000300175.9	c.-32A>T		5_prime_UTR_variant	1/6	1	NM_001144757.3	ENSP00000300175.4
ARHGAP11A-SCG5	ENST00000692248.1	c.1236-1832A>T		intron_variant				ENSP00000510771.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16674 AN: 152086 Hom.: 1119 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.207 AC: 24 AN: 116 Hom.: 3 Cov.: 0 AF XY: 0.207 AC XY: 17 AN XY: 82

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.110 AC: 16671 AN: 152206 Hom.: 1119 Cov.: 32 AF XY: 0.107 AC XY: 7992 AN XY: 74416

Gnomad4 AFR AF: 0.0481

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0164

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.115

Alfa AF: 0.134 Hom.: 207

Bravo AF: 0.104

Asia WGS AF: 0.0570 AC: 202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0070
DANN	Benign	0.66

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: rs13850; hg19: chr15-32933955;