rs2059610523

Variant names:

• chr9-121299873-C-G
• rs2059610523
• ENST00000373818.8:c.12C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000177.5(GSN):​c.12C>G​(p.His4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSN NM_000177.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.921
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056847006).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000177.5. 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.-9-2090C>G		intron	N/A	NP_937895.1	P06396-2
	GSN	NM_000177.5		c.12C>G	p.His4Gln	missense	Exon 1 of 17	NP_000168.1	P06396-1
	GSN	NM_001127663.2		c.100-2090C>G		intron	N/A	NP_001121135.2	A0A0A0MT01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSN	ENST00000373818.8	TSL:1	c.12C>G	p.His4Gln	missense	Exon 1 of 17	ENSP00000362924.4	P06396-1
	GSN	ENST00000432226.7	TSL:5 MANE Select	c.-9-2090C>G		intron	N/A	ENSP00000404226.2	P06396-2
	GSN	ENST00000900632.1		c.-142C>G		5_prime_UTR	Exon 1 of 18	ENSP00000570691.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000255 AC: 3 AN: 1175748 Hom.: 0 Cov.: 30 AF XY: 0.00000349 AC XY: 2 AN XY: 572328

African (AFR) AF: 0.00 AC: 0 AN: 23712

American (AMR) AF: 0.00 AC: 0 AN: 16548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18102

East Asian (EAS) AF: 0.00 AC: 0 AN: 24826

South Asian (SAS) AF: 0.00 AC: 0 AN: 48760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3296

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 963398

Other (OTH) AF: 0.00 AC: 0 AN: 46390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.1
DANN	Benign	0.84
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.92
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.012
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.092		Gain of solvent accessibility (P = 0.0338)
MVP		0.19
MPC		1.1
ClinPred		0.17	T
GERP RS		-2.6
PromoterAI		-0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.073
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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: rs2059610523; hg19: chr9-124062151;