rs774996980

chr5-128344493-C-Achr5-128344493-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 3P and 18B. PM1 PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):c.3235G>T(p.Ala1079Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1079V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.41

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001999.4
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.11250788).
• BP6: Variant 5-128344493-C-A is Benign according to our data. Variant chr5-128344493-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 213302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128344493-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000158 (24/152252) while in subpopulation AMR AF= 0.00111 (17/15288). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3235G>T	p.Ala1079Ser	missense_variant	25/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3082G>T	p.Ala1028Ser	missense_variant	24/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3235G>T	p.Ala1079Ser	missense_variant	25/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.3136G>T	p.Ala1046Ser	missense_variant	24/33	2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251386 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;.;.;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.16	N;.;N;.
MutationTaster	Benign	0.77	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N;.;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.47	T;.;T;T
Polyphen		0.017	B;.;B;B
Vest4		0.28
MutPred		0.53		Loss of ubiquitination at K1078 (P = 0.1453);.;Loss of ubiquitination at K1078 (P = 0.1453);.;
MVP		0.45
MPC		0.30
ClinPred		0.037	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs774996980; hg19: chr5-127680185;