NM_032447.5:c.6031+141G>A

Variant names:

• chr19-8091324-C-T
• rs8112982
• NM_032447.5:c.6031+141G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_032447.5(FBN3):c.6031+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0152 (AC=17,471) in the gnomAD database across 1,149,846 control chromosomes, including 1,446 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.198. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.059 (869 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (577 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 1 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1979 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FBN3 NM_032447.5	MANE Select	c.6031+141G>A	intron	Intron 48 of 63	Prot: NP_115823.3
	FBN3 NM_001321431.2		c.6031+141G>A	intron	Intron 48 of 63	Prot: NP_001308360.1 UniProt:

FBN3 NM_032447.5

MANE Select

HGVSc / HGVSpc.6031+141G>A

Exon rankIntron 48 of 63

intron

Prot: NP_115823.3

FBN3 NM_001321431.2

HGVSc / HGVSpc.6031+141G>A

Exon rankIntron 48 of 63

intron

Prot: NP_001308360.1UniProt: Q75N90

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FBN3 ENST00000600128.6	TSL:1MANE Select	c.6031+141G>A	intron	Intron 48 of 63	Prot: ENSP00000470498.1 UniProt:
	FBN3 ENST00000270509.6	TSL:1	c.6031+141G>A	intron	Intron 47 of 62	Prot: ENSP00000270509.2 UniProt:
	FBN3 ENST00000601739.5	TSL:1	c.6031+141G>A	intron	Intron 48 of 63	Prot: ENSP00000472324.1 UniProt:

FBN3 ENST00000600128.6

TSL:1MANE Select

HGVSc / HGVSpc.6031+141G>A

Exon rankIntron 48 of 63

intron

Prot: ENSP00000470498.1UniProt: Q75N90

FBN3 ENST00000270509.6

TSL:1

HGVSc / HGVSpc.6031+141G>A

Exon rankIntron 47 of 62

intron

Prot: ENSP00000270509.2UniProt: Q75N90

FBN3 ENST00000601739.5

TSL:1

HGVSc / HGVSpc.6031+141G>A

Exon rankIntron 48 of 63

intron

Prot: ENSP00000472324.1UniProt: Q75N90

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0593	AC:9025	Hom:864	AN:152138	Cov:32
GnomAD4 exome	AF: 0.00844	AC:8415	Hom:577	AN:997590	Cov:
GnomAD4 genome	AF: 0.0595	AC:9056	Hom:869	AN:152256	Cov:32
TOPMed (Bravo)	AF: 0.0674	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0529	AC:1440	Hom:149	AN:27230	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0500	AC:117	Hom:7	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0249	AC:	Hom:	AN:	Cov:
GenomeAsia100K	AF: 0.0350	AC:123	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.00885	AC:64	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0341	AC:6	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0180	AC:2214	Hom:25	AN:122690	Cov:
Turkish Variome	AF: 0.00130	AC:2	Hom:0	AN:1544	Cov:
UK10K	AF: 0.000529	AC:4	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0269	AC:241	Hom:5	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00330	216	65496	0.00236	280	118804

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.1
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.39
GPN-Star LLR	N/A	0.46
GPN-Star score	N/A	-0.46
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.058

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs8112982;

hg19: chr19-8156208;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar