15-32684639-G-A

Variant names:

• chr15-32684639-G-A
• rs35500536
• NM_001144757.3:c.459G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001144757.3(SCG5):​c.459G>A​(p.Pro153Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,494 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: SCG5 NM_001144757.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.312
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-32684639-G-A is Benign according to our data. Variant chr15-32684639-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1316231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.312 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1116/152302) while in subpopulation AFR AF = 0.0245 (1019/41556). AF 95% confidence interval is 0.0233. There are 11 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144757.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCG5	NM_001144757.3	MANE Select	c.459G>A	p.Pro153Pro	synonymous	Exon 4 of 6	NP_001138229.1	P05408-1
	ARHGAP11A-SCG5	NM_001368319.1		c.1698G>A	p.Pro566Pro	synonymous	Exon 12 of 14	NP_001355248.1	A0A8I5KWH8
	SCG5	NM_003020.5		c.456G>A	p.Pro152Pro	synonymous	Exon 4 of 6	NP_003011.1	P05408-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCG5	ENST00000300175.9	TSL:1 MANE Select	c.459G>A	p.Pro153Pro	synonymous	Exon 4 of 6	ENSP00000300175.4	P05408-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.1698G>A	p.Pro566Pro	synonymous	Exon 12 of 14	ENSP00000510771.1	A0A8I5KWH8
	SCG5	ENST00000413748.6	TSL:1	c.456G>A	p.Pro152Pro	synonymous	Exon 4 of 6	ENSP00000388560.2	P05408-2

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1110 AN: 152184 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.000588

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00195 AC: 484 AN: 248622 AF XY: 0.00151

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00120 AC: 1754 AN: 1461192 Hom.: 8 Cov.: 29 AF XY: 0.00110 AC XY: 798 AN XY: 726820

African (AFR) AF: 0.0249 AC: 833 AN: 33466

American (AMR) AF: 0.00123 AC: 55 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86110

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53398

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000645 AC: 717 AN: 1111566

Other (OTH) AF: 0.00222 AC: 134 AN: 60354

GnomAD4 genome AF: 0.00733 AC: 1116 AN: 152302 Hom.: 11 Cov.: 33 AF XY: 0.00643 AC XY: 479 AN XY: 74470

African (AFR) AF: 0.0245 AC: 1019 AN: 41556

American (AMR) AF: 0.00294 AC: 45 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00426 Hom.: 5

Bravo AF: 0.00811

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000772

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		0.31
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35500536; hg19: chr15-32976840;