rs200837433

Variant names:

• chr5-128330672-T-C
• rs200837433
• NM_001999.4:c.4246A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 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. 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
• Publications: 6 publications found

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]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_001999.4
• 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 VariationId is 213409.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. 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
	FBN2	NM_001999.4	MANE Select	c.4246A>G	p.Thr1416Ala	missense	Exon 33 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.4246A>G	p.Thr1416Ala	missense	Exon 33 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.4147A>G	p.Thr1383Ala	missense	Exon 32 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.4093A>G	p.Thr1365Ala	missense	Exon 32 of 64	ENSP00000609463.1

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

GnomAD2 exomes AF: 0.000720 AC: 181 AN: 251304 AF XY: 0.000655

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.000693 AC: 31 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000518 AC: 576 AN: 1111862

Other (OTH) AF: 0.000315 AC: 19 AN: 60390

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

African (AFR) AF: 0.000145 AC: 6 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000417 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital contractural arachnodactyly (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.097	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.53
Sift	Benign	0.039	D
Sift4G	Benign	0.66	T
Polyphen		0.24	B
Vest4		0.58
MVP		0.78
MPC		0.25
ClinPred		0.094	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.56
Mutation Taster		=72/28	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: rs200837433; hg19: chr5-127666364;