rs12683459

Variant names:

• chr9-121286020-G-A
• rs12683459
• NM_198252.3:c.-10+4458G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198252.3(GSN):​c.-10+4458G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,054,198 control chromosomes in the GnomAD database, including 20,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3911 hom., cov: 33)
  • Exomes 𝑓: 0.18 (16394 hom.)
• Consequence: GSN NM_198252.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.105
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Finnish type amyloidosis

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000239593 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-121286020-G-A is Benign according to our data. Variant chr9-121286020-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198252.3. 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
	GSN	NM_198252.3	MANE Select	c.-10+4458G>A		intron	N/A	NP_937895.1	P06396-2
	GSN	NM_001127663.2		c.99+3470G>A		intron	N/A	NP_001121135.2	A0A0A0MT01
	GSN	NM_001353076.2		c.-48+4458G>A		intron	N/A	NP_001340005.1	A0A8V8TND7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSN	ENST00000432226.7	TSL:5 MANE Select	c.-10+4458G>A		intron	N/A	ENSP00000404226.2	P06396-2
	GSN	ENST00000900575.1		c.-10+4458G>A		intron	N/A	ENSP00000570634.1
	GSN	ENST00000449733.7	TSL:2	c.99+3470G>A		intron	N/A	ENSP00000409358.2	A0A0A0MT01

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32560 AN: 152090 Hom.: 3908 Cov.: 33

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.184 AC: 165661 AN: 901990 Hom.: 16394 AF XY: 0.181 AC XY: 83994 AN XY: 463504

African (AFR) AF: 0.321 AC: 7167 AN: 22352

American (AMR) AF: 0.129 AC: 4473 AN: 34622

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2522 AN: 21946

East Asian (EAS) AF: 0.0584 AC: 1956 AN: 33488

South Asian (SAS) AF: 0.130 AC: 9012 AN: 69074

European-Finnish (FIN) AF: 0.186 AC: 6149 AN: 33114

Middle Eastern (MID) AF: 0.114 AC: 544 AN: 4762

European-Non Finnish (NFE) AF: 0.198 AC: 126704 AN: 640608

Other (OTH) AF: 0.170 AC: 7134 AN: 42024

GnomAD4 genome AF: 0.214 AC: 32584 AN: 152208 Hom.: 3911 Cov.: 33 AF XY: 0.210 AC XY: 15605 AN XY: 74418

African (AFR) AF: 0.324 AC: 13437 AN: 41502

American (AMR) AF: 0.142 AC: 2169 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3472

East Asian (EAS) AF: 0.0532 AC: 276 AN: 5188

South Asian (SAS) AF: 0.123 AC: 595 AN: 4824

European-Finnish (FIN) AF: 0.183 AC: 1942 AN: 10604

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13315 AN: 67998

Other (OTH) AF: 0.170 AC: 359 AN: 2116

Alfa AF: 0.204 Hom.: 1662

Bravo AF: 0.212

Asia WGS AF: 0.124 AC: 431 AN: 3476

ClinVar

ClinVar submissions

Significance: 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	-0.79
CADD	Benign	2.2
DANN	Benign	0.75
PhyloP100		0.10
PromoterAI		-0.22	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12683459; hg19: chr9-124048298; COSMIC: COSV107439293; COSMIC: COSV107439293;