9-121286183-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198252.3(GSN):c.-10+4621T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,529,228 control chromosomes in the GnomAD database, including 2,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (624 hom., cov: 32)
  • Exomes 𝑓: 0.025 (1974 hom.)
• Consequence: GSN NM_198252.3 intron
• Scores: Splicing: ADA: 0.00002783
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.887

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016709864).
• BP6: Variant 9-121286183-T-C is Benign according to our data. Variant chr9-121286183-T-C is described in ClinVar as [Benign]. Clinvar id is 1267128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSN	NM_198252.3	c.-10+4621T>C		intron_variant		ENST00000432226.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSN	ENST00000432226.7	c.-10+4621T>C		intron_variant		5	NM_198252.3	P1

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9574 AN: 152072 Hom.: 622 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0809 AC: 10358 AN: 128050 Hom.: 922 AF XY: 0.0704 AC XY: 4939 AN XY: 70128

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.0722

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.00956

Gnomad OTH exome AF: 0.0476

GnomAD4 exome AF: 0.0254 AC: 35006 AN: 1377038 Hom.: 1974 Cov.: 29 AF XY: 0.0260 AC XY: 17682 AN XY: 679928

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.0733

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0630 AC: 9589 AN: 152190 Hom.: 624 Cov.: 32 AF XY: 0.0663 AC XY: 4935 AN XY: 74408

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0851

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0287 Hom.: 64

Bravo AF: 0.0774

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00804 AC: 31

ExAC AF: 0.0361 AC: 637

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	12
Dann	Benign	0.48
DEOGEN2	Benign	0.0089	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0017	T
MutationTaster	Benign	0.28	P;P;P;P;P;P;P
Sift4G	Benign	0.83	T
Vest4		0.13
GERP RS		-0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.080		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: rs12343736; hg19: chr9-124048461; COSMIC: COSV100375830; COSMIC: COSV100375830;