19-8136167-T-C

Variant names:

• chr19-8136167-T-C
• rs8112525
• NM_032447.5:c.1465+23A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032447.5(FBN3):​c.1465+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,613,478 control chromosomes in the GnomAD database, including 676,152 homozygotes. 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: 𝑓 0.92 (65027 hom., cov: 31)
  • Exomes 𝑓: 0.91 (611125 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.1465+23A>G		intron	N/A	NP_115823.3
	FBN3	NM_001321431.2		c.1465+23A>G		intron	N/A	NP_001308360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.1465+23A>G		intron	N/A	ENSP00000470498.1
	FBN3	ENST00000270509.6	TSL:1	c.1465+23A>G		intron	N/A	ENSP00000270509.2
	FBN3	ENST00000601739.5	TSL:1	c.1465+23A>G		intron	N/A	ENSP00000472324.1

Frequencies

GnomAD3 genomes AF: 0.924 AC: 140442 AN: 152072 Hom.: 64974 Cov.: 31

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.931

GnomAD2 exomes AF: 0.911 AC: 227768 AN: 250122 AF XY: 0.910

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.941

Gnomad ASJ exome AF: 0.927

Gnomad EAS exome AF: 0.747

Gnomad FIN exome AF: 0.899

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.914 AC: 1335461 AN: 1461288 Hom.: 611125 Cov.: 81 AF XY: 0.914 AC XY: 664331 AN XY: 726942

African (AFR) AF: 0.958 AC: 32088 AN: 33480

American (AMR) AF: 0.938 AC: 41887 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 24089 AN: 26096

East Asian (EAS) AF: 0.735 AC: 29172 AN: 39700

South Asian (SAS) AF: 0.918 AC: 79139 AN: 86178

European-Finnish (FIN) AF: 0.902 AC: 48021 AN: 53224

Middle Eastern (MID) AF: 0.891 AC: 5138 AN: 5766

European-Non Finnish (NFE) AF: 0.918 AC: 1021143 AN: 1111832

Other (OTH) AF: 0.907 AC: 54784 AN: 60376

GnomAD4 genome AF: 0.924 AC: 140554 AN: 152190 Hom.: 65027 Cov.: 31 AF XY: 0.921 AC XY: 68526 AN XY: 74408

African (AFR) AF: 0.955 AC: 39676 AN: 41534

American (AMR) AF: 0.929 AC: 14203 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3209 AN: 3472

East Asian (EAS) AF: 0.755 AC: 3891 AN: 5152

South Asian (SAS) AF: 0.915 AC: 4410 AN: 4820

European-Finnish (FIN) AF: 0.887 AC: 9414 AN: 10608

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.922 AC: 62667 AN: 68004

Other (OTH) AF: 0.931 AC: 1965 AN: 2110

Alfa AF: 0.920 Hom.: 120668

Bravo AF: 0.927

Asia WGS AF: 0.868 AC: 3021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.52
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8112525; hg19: chr19-8201051;