5-128258040-C-T

Variant names:

• chr5-128258040-C-T
• rs1050687
• NM_001999.4:c.*1415G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001999.4(FBN2):​c.*1415G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 151,806 control chromosomes in the GnomAD database, including 7,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (7980 hom., cov: 32)
  • Exomes 𝑓: 0.16 (4 hom.)
• Consequence: FBN2 NM_001999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.390

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-128258040-C-T is Benign according to our data. Variant chr5-128258040-C-T is described in ClinVar as [Benign]. Clinvar id is 350729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.*1415G>A		3_prime_UTR_variant	Exon 65 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.*1415G>A		3_prime_UTR_variant	Exon 64 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464	c.*1415G>A		3_prime_UTR_variant	Exon 65 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37556 AN: 151268 Hom.: 7949 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.164 AC: 71 AN: 432 Hom.: 4 Cov.: 0 AF XY: 0.185 AC XY: 48 AN XY: 260

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.249 AC: 37636 AN: 151374 Hom.: 7980 Cov.: 32 AF XY: 0.244 AC XY: 18049 AN XY: 73952

Gnomad4 AFR AF: 0.586

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.0404

Gnomad4 SAS AF: 0.0718

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.195

Alfa AF: 0.113 Hom.: 624

Bravo AF: 0.264

Asia WGS AF: 0.0910 AC: 317 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.34

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: rs1050687; hg19: chr5-127593732; COSMIC: COSV52536600;