rs200837433

chr5-128330672-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_001999.4(FBN2):c.4246A>G(p.Thr1416Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1416I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.15

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 -8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_001999.4
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.09717208).
• BP6: Variant 5-128330672-T-C is Benign according to our data. Variant chr5-128330672-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213409.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr5-128330672-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000375 (57/152138) while in subpopulation NFE AF= 0.000353 (24/68030). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4246A>G	p.Thr1416Ala	missense_variant	33/65	ENST00000262464.9
FBN2	XM_017009228.3	c.4093A>G	p.Thr1365Ala	missense_variant	32/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4246A>G	p.Thr1416Ala	missense_variant	33/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000720 AC: 181 AN: 251304 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.000906

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 352 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.000518

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74322

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000997 AC: 121

EpiCase AF: 0.000763

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2016

The T1416A variant in the FBN2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T1416A variant was observed on 0.27% alleles from individuals of Finnish background in the Exome Aggregation Consortium (ExAC) data set. The T1416A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1416A as a variant of uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2019

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. -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

FBN2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;D;D;D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;.;.;D;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.097	T;T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.1	L;.;L;.;.
MutationTaster	Benign	0.73	D;D;D;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.039	D;.;D;T;T
Polyphen		0.24	B;.;B;.;P
Vest4		0.58
MVP		0.78
MPC		0.25
ClinPred		0.094	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.56

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: rs200837433; hg19: chr5-127666364;