Genetic Variant FSD2:p.Phe671Leu (chr15-82759587-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001007122.4(FSD2):c.2011T>C(p.Phe671Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,426,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FSD2
NM_001007122.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.53

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSD2	NM_001007122.4 link	c.2011T>C	p.Phe671Leu	missense_variant	Exon 13 of 13	ENST00000334574.12	NP_001007123.1	A1L4K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSD2	ENST00000334574.12 link	c.2011T>C	p.Phe671Leu	missense_variant	Exon 13 of 13	1	NM_001007122.4	ENSP00000335651.8		A1L4K1-1
FSD2	ENST00000541889.1 link	c.1876T>C	p.Phe626Leu	missense_variant	Exon 12 of 12	1		ENSP00000444078.1		A1L4K1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000489

AC:

AN:

204604

Hom.:

AF XY:

0.00000912

AC XY:

AN XY:

109612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000362

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1426696

Hom.:

Cov.:

AF XY:

0.00000425

AC XY:

AN XY:

706088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2011T>C (p.F671L) alteration is located in exon 13 (coding exon 12) of the FSD2 gene. This alteration results from a T to C substitution at nucleotide position 2011, causing the phenylalanine (F) at amino acid position 671 to be replaced by a leucine (L). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.39

Sift

Benign

0.16

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;.

Vest4

0.53

MutPred

0.54

Loss of sheet (P = 0.0817);.;

MVP

0.36

MPC

0.36

ClinPred

0.97

GERP RS

5.7

Varity_R

0.59

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over