12-132490581-A-G

Variant names:

• chr12-132490581-A-G
• rs1348823968
• NM_001367871.1:c.11A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001367871.1(FBRSL1):​c.11A>G​(p.Lys4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 981,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1182991).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 19	ENST00000680143.1	NP_001354800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBRSL1	ENST00000680143.1	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.11A>G	p.Lys4Arg	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146038 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 16 AN: 835846 Hom.: 0 Cov.: 28 AF XY: 0.0000207 AC XY: 8 AN XY: 386200

African (AFR) AF: 0.00 AC: 0 AN: 15814

American (AMR) AF: 0.00 AC: 0 AN: 1056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5200

East Asian (EAS) AF: 0.00 AC: 0 AN: 3672

South Asian (SAS) AF: 0.00 AC: 0 AN: 17250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1626

European-Non Finnish (NFE) AF: 0.0000210 AC: 16 AN: 763354

Other (OTH) AF: 0.00 AC: 0 AN: 27424

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146038 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 71046

African (AFR) AF: 0.00 AC: 0 AN: 40668

American (AMR) AF: 0.0000679 AC: 1 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65794

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11A>G (p.K4R) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a A to G substitution at nucleotide position 11, causing the lysine (K) at amino acid position 4 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.27
DEOGEN2	Benign	0.0037	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		1.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.10
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.22	T;.
Polyphen		0.94	P;.
Vest4		0.14
MutPred		0.28		Loss of ubiquitination at K4 (P = 0.0546);Loss of ubiquitination at K4 (P = 0.0546);
MVP		0.014
ClinPred		0.21	T
GERP RS		2.1
PromoterAI		-0.24	Neutral
Varity_R		0.066
gMVP		0.097
Mutation Taster		=85/15	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: rs1348823968; hg19: chr12-133067167;