chr5-128537531-C-T

Variant names:

• chr5-128537531-C-T
• rs763408652
• NM_001999.4:c.73G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001999.4(FBN2):​c.73G>A​(p.Gly25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,902 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.15

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15409392).
• BP6: Variant 5-128537531-C-T is Benign according to our data. Variant chr5-128537531-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569505.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000986 AC: 2 AN: 202838 Hom.: 0 AF XY: 0.00000902 AC XY: 1 AN XY: 110878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000658

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434902 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 711876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Apr 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G25S variant (also known as c.73G>A), located in coding exon 1 of the FBN2 gene, results from a G to A substitution at nucleotide position 73. The glycine at codon 25 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Oct 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:1

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	D;.;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-0.46	N;.;N;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.59	N;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.032	D;.;D;D;D
Sift4G	Benign	0.063	.;.;.;T;D
Polyphen		0.88	P;.;P;P;B
Vest4		0.15
MutPred		0.36		Gain of glycosylation at G25 (P = 0.002);Gain of glycosylation at G25 (P = 0.002);Gain of glycosylation at G25 (P = 0.002);Gain of glycosylation at G25 (P = 0.002);Gain of glycosylation at G25 (P = 0.002);
MVP		0.26
MPC		0.23
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.65

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: rs763408652; hg19: chr5-127873224;