Genetic Variant GSN:c.-10+1754dupT (chr9-121283301-C-CT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.469

Publications

1 publications found

Variant links:

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 links:

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

GSN-AS1 links:

ENSG00000239593 (HGNC:):

ENSG00000239593 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353074.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSN	NM_198252.3	MANE Select	c.-10+1754dupT	intron	N/A	NP_937895.1	P06396-2
GSN	NM_001127663.2		c.99+766dupT	intron	N/A	NP_001121135.2	A0A0A0MT01
GSN	NM_001353076.2		c.-48+1754dupT	intron	N/A	NP_001340005.1	A0A8V8TND7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSN	ENST00000432226.7	TSL:5 MANE Select	c.-10+1754dupT	intron	N/A	ENSP00000404226.2	P06396-2
GSN	ENST00000972594.1		c.-86dupT	5_prime_UTR	Exon 2 of 18	ENSP00000642653.1
GSN	ENST00000900575.1		c.-10+1754dupT	intron	N/A	ENSP00000570634.1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

165

AN:

136052

Hom.:

Cov.:

show subpopulations

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:

AN:

4716

Hom.:

Cov.:

AF XY:

0.00311

AC XY:

AN XY:

2248

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00303

AC:

AN:

4628

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0200

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00121

AC:

165

AN:

136054

Hom.:

Cov.:

AF XY:

0.000919

AC XY:

AN XY:

65306

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

37328

American (AMR)

AF:

0.000220

AC:

AN:

13640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3302

East Asian (EAS)

AF:

0.000213

AC:

AN:

4686

South Asian (SAS)

AF:

0.000242

AC:

AN:

4140

European-Finnish (FIN)

AF:

0.00127

AC:

AN:

7098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

62902

Other (OTH)

AF:

0.00108

AC:

AN:

1848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000347

Hom.:

340

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Finnish type amyloidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over