9-121283301-C-CT

Variant names:

• chr9-121283301-C-CT
• rs56834014
• NM_198252.3:c.-10+1754dupT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001353074.2(GSN):​c.-121-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (0 hom.)
• Consequence: GSN NM_001353074.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.469

Genes affected

GSN (HGNC:4620): (gelsolin) The protein encoded by this gene binds to the "plus" ends of actin monomers and filaments to prevent monomer exchange. The encoded calcium-regulated protein functions in both assembly and disassembly of actin filaments. Defects in this gene are a cause of familial amyloidosis Finnish type (FAF). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GSN-AS1 (HGNC:23372): (GSN antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.033198744 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: tcttttttttttttttttAGacg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BS2: High AC in GnomAd4 at 165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSN	NM_198252.3	c.-10+1754dupT		intron_variant	Intron 2 of 17	ENST00000432226.7	NP_937895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSN	ENST00000432226.7	c.-10+1754dupT		intron_variant	Intron 2 of 17	5	NM_198252.3	ENSP00000404226.2

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 165 AN: 136052 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000220

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00109

GnomAD4 exome AF: 0.00318 AC: 15 AN: 4716 Hom.: 0 Cov.: 0 AF XY: 0.00311 AC XY: 7 AN XY: 2248

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00121 AC: 165 AN: 136054 Hom.: 0 Cov.: 0 AF XY: 0.000919 AC XY: 60 AN XY: 65306

Gnomad4 AFR AF: 0.00182

Gnomad4 AMR AF: 0.000220

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000213

Gnomad4 SAS AF: 0.000242

Gnomad4 FIN AF: 0.00127

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00108

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Finnish type amyloidosis Uncertain:1

May 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

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: rs56834014; hg19: chr9-124045579;