chr5-128258722-A-T

Position:

• chr5-128258722-A-T

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.*733T>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 0.262 in 152,650 control chromosomes in the GnomAD database, including 9,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (9214 hom., cov: 32)
  • Exomes 𝑓: 0.16 (5 hom.)
• Consequence: FBN2 NM_001999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0660

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=-0.55).
• BP6: Variant 5-128258722-A-T is Benign according to our data. Variant chr5-128258722-A-T is described in ClinVar as [Benign]. Clinvar id is 350741.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.*733T>A		3_prime_UTR_variant	65/65	ENST00000262464.9
FBN2	XM_017009228.3	c.*733T>A		3_prime_UTR_variant	64/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.*733T>A		3_prime_UTR_variant	65/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39878 AN: 151974 Hom.: 9178 Cov.: 32

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0725

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.158 AC: 88 AN: 558 Hom.: 5 Cov.: 0 AF XY: 0.173 AC XY: 61 AN XY: 352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.263 AC: 39967 AN: 152092 Hom.: 9214 Cov.: 32 AF XY: 0.258 AC XY: 19160 AN XY: 74342

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.0763

Gnomad4 EAS AF: 0.0403

Gnomad4 SAS AF: 0.0723

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.205

Alfa AF: 0.210 Hom.: 743

Bravo AF: 0.278

Asia WGS AF: 0.0850 AC: 297 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.55
CADD	Benign	4.8
DANN	Benign	0.75

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: rs13305; hg19: chr5-127594414; COSMIC: COSV52501095;