chr12-132490718-C-T

Variant names:

• chr12-132490718-C-T
• rs1252866744
• NM_001367871.1:c.148C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001367871.1(FBRSL1):​c.148C>T​(p.Arg50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 986,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.433
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17076328).

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.148C>T	p.Arg50Cys	missense	Exon 1 of 19	NP_001354800.1	A0A7P0Z485
	FBRSL1	NM_001142641.2		c.148C>T	p.Arg50Cys	missense	Exon 1 of 17	NP_001136113.1	Q9HCM7
	FBRSL1	NM_001382739.1		c.148C>T	p.Arg50Cys	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.148C>T	p.Arg50Cys	missense	Exon 1 of 19	ENSP00000505341.1	A0A7P0Z485
	FBRSL1	ENST00000434748.2	TSL:1	c.148C>T	p.Arg50Cys	missense	Exon 1 of 17	ENSP00000396160.2	Q9HCM7
	FBRSL1	ENST00000955044.1		c.148C>T	p.Arg50Cys	missense	Exon 1 of 20	ENSP00000625103.1

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 9 AN: 840390 Hom.: 0 Cov.: 28 AF XY: 0.00000771 AC XY: 3 AN XY: 388958

⚠️ 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: 15924

American (AMR) AF: 0.00 AC: 0 AN: 1642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5584

East Asian (EAS) AF: 0.00 AC: 0 AN: 3792

South Asian (SAS) AF: 0.00 AC: 0 AN: 17804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1660

European-Non Finnish (NFE) AF: 0.0000118 AC: 9 AN: 765580

Other (OTH) AF: 0.00 AC: 0 AN: 27650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00132055), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71062

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

African (AFR) AF: 0.00 AC: 0 AN: 40758

American (AMR) AF: 0.00 AC: 0 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65798

Other (OTH) AF: 0.00 AC: 0 AN: 2016

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.43
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.071
Sift	Benign	0.031	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.088
MutPred		0.38		Loss of methylation at R50 (P = 0.0121)
MVP		0.33
ClinPred		0.53	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.10
gMVP		0.17
Mutation Taster		=99/1	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: rs1252866744; hg19: chr12-133067304;