9-121282470-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198252.3(GSN):c.-10+908C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,267,542 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: GSN NM_198252.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0570

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)

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040370256).
• BP6: Variant 9-121282470-C-T is Benign according to our data. Variant chr9-121282470-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3058775.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000381 (58/152316) while in subpopulation SAS AF= 0.000622 (3/4826). AF 95% confidence interval is 0.000292. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSN	NM_198252.3	c.-10+908C>T		intron_variant		ENST00000432226.7
GSN-AS1	NR_103560.1	n.3061G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSN	ENST00000432226.7	c.-10+908C>T		intron_variant		5	NM_198252.3	P1
GSN-AS1	ENST00000414544.1	n.3061G>A		non_coding_transcript_exon_variant	1/1
	ENST00000437135.1	n.261G>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000352 AC: 393 AN: 1115226 Hom.: 2 Cov.: 28 AF XY: 0.000349 AC XY: 184 AN XY: 527884

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000815

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00213

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.000493

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GSN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	4.9
Dann	Benign	0.70
DEOGEN2	Benign	0.0061	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.040	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
Vest4		0.041
MVP		0.67
GERP RS		0.96

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: rs145775883; hg19: chr9-124044748;