Genetic Variant FSD2:p.Arg391Gly (chr15-82772169-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001007122.4(FSD2):c.1171C>G(p.Arg391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FSD2
NM_001007122.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

Publications

0 publications found

Variant links:

Genes affected

FSD2 (HGNC:18024): (fibronectin type III and SPRY domain containing 2) This gene encodes a protein that belongs to the FN3/SPRY family of proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

FSD2 links:

SNHG21 (HGNC:50284): (small nucleolar RNA host gene 21)

SNHG21 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSD2	NM_001007122.4 link	c.1171C>G	p.Arg391Gly	missense_variant	Exon 7 of 13	ENST00000334574.12	NP_001007123.1	A1L4K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FSD2	ENST00000334574.12 link	c.1171C>G	p.Arg391Gly	missense_variant	Exon 7 of 13	1	NM_001007122.4	ENSP00000335651.8	A1L4K1-1
FSD2	ENST00000541889.1 link	c.1171C>G	p.Arg391Gly	missense_variant	Exon 7 of 12	1		ENSP00000444078.1	A1L4K1-2
SNHG21	ENST00000834480.1 link	n.434+17385G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460270

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

85734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111372

Other (OTH)

AF:

0.00

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000478

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1171C>G (p.R391G) alteration is located in exon 7 (coding exon 6) of the FSD2 gene. This alteration results from a C to G substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.5

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.18

Sift

Benign

0.052

T;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.98

D;.

Vest4

0.81

MutPred

0.68

Gain of catalytic residue at V392 (P = 0.0121);Gain of catalytic residue at V392 (P = 0.0121);

MVP

0.63

MPC

0.36

ClinPred

0.94

GERP RS

4.3

Varity_R

0.18

gMVP

0.72

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over