19-8083430-A-T

Variant names:

• chr19-8083430-A-T
• rs17160149
• NM_032447.5:c.7088-58T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032447.5(FBN3):​c.7088-58T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 0 publications found

Genes affected

FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.7088-58T>A		intron_variant	Intron 56 of 63	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.7088-58T>A		intron_variant	Intron 56 of 63	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.7088-58T>A		intron_variant	Intron 55 of 62	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.7088-58T>A		intron_variant	Intron 56 of 63	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.7214-58T>A		intron_variant	Intron 56 of 63			ENSP00000498507.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446000 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 719466

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.0000224 AC: 1 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102246

Other (OTH) AF: 0.00 AC: 0 AN: 59976

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.0
DANN	Benign	0.21
PhyloP100		-0.030

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: rs17160149; hg19: chr19-8148314;