12-132490689-C-A

Variant names:

• chr12-132490689-C-A
• rs1194276361
• NM_001367871.1:c.119C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367871.1(FBRSL1):​c.119C>A​(p.Pro40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000117 in 852,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.454
• Publications: 0 publications found

Genes affected

FBRSL1 (HGNC:29308): (fibrosin like 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

FBRSL1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Broad Center for Mendelian Genomics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19157213).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367871.1. 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
	FBRSL1	NM_001367871.1	MANE Select	c.119C>A	p.Pro40His	missense	Exon 1 of 19	NP_001354800.1	A0A7P0Z485
	FBRSL1	NM_001142641.2		c.119C>A	p.Pro40His	missense	Exon 1 of 17	NP_001136113.1	Q9HCM7
	FBRSL1	NM_001382739.1		c.119C>A	p.Pro40His	missense	Exon 1 of 19	NP_001369668.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBRSL1	ENST00000680143.1	MANE Select	c.119C>A	p.Pro40His	missense	Exon 1 of 19	ENSP00000505341.1	A0A7P0Z485
	FBRSL1	ENST00000434748.2	TSL:1	c.119C>A	p.Pro40His	missense	Exon 1 of 17	ENSP00000396160.2	Q9HCM7
	FBRSL1	ENST00000955044.1		c.119C>A	p.Pro40His	missense	Exon 1 of 20	ENSP00000625103.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 852548 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 396118

⚠️ 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: 16146

American (AMR) AF: 0.000225 AC: 1 AN: 4454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6768

East Asian (EAS) AF: 0.00 AC: 0 AN: 3776

South Asian (SAS) AF: 0.00 AC: 0 AN: 20736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 769638

Other (OTH) AF: 0.00 AC: 0 AN: 28132

⚠️ 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.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.45
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.063
Sift	Benign	0.054	T
Sift4G	Uncertain	0.055	T
Polyphen		0.23	B
Vest4		0.13
MutPred		0.18		Loss of glycosylation at P40 (P = 0.0671)
MVP		0.11
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.090
gMVP		0.18
Mutation Taster		=90/10	polymorphism

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: rs1194276361; hg19: chr12-133067275;