16-30665077-A-G

Variant names:

• chr16-30665077-A-G
• NM_001105079.3:c.1606A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001105079.3(FBRS):​c.1606A>G​(p.Asn536Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBRS NM_001105079.3 missense, splice_region
• Scores: Splicing: ADA: 0.08392
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

Genes affected

FBRS (HGNC:20442): (fibrosin) Fibrosin is a lymphokine secreted by activated lymphocytes that induces fibroblast proliferation (Prakash and Robbins, 1998 [PubMed 9809749]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.76428 (below the threshold of 3.09). Trascript score misZ: -2.0176 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.31902137).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105079.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBRS	NM_001105079.3	MANE Select	c.1606A>G	p.Asn536Asp	missense splice_region	Exon 9 of 18	NP_001098549.2	J3KNZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBRS	ENST00000356166.11	TSL:5 MANE Select	c.1606A>G	p.Asn536Asp	missense splice_region	Exon 9 of 18	ENSP00000348489.5	J3KNZ9
	FBRS	ENST00000287468.5	TSL:5	c.46A>G	p.Asn16Asp	missense splice_region	Exon 3 of 12	ENSP00000287468.5	Q9HAH7-2
	FBRS	ENST00000543786.5	TSL:2	n.585-1842A>G		intron	N/A	ENSP00000456204.1	H3BRE6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460928 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726784

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.087
Sift	Uncertain	0.012	D
Sift4G	Benign	0.36	T
Polyphen		0.99	D
Vest4		0.51
MutPred		0.30		Gain of disorder (P = 0.1456)
MVP		0.12
MPC		1.1
ClinPred		0.72	D
GERP RS		4.4
Varity_R		0.27
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.084
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.020		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

hg19: chr16-30676398;