rs1223506294

Variant names:

• chr12-132508211-A-G
• rs1223506294
• NM_001367871.1:c.350A>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.350A>G​(p.Lys117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,551,106 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 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.140
• 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=0.19917554).
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.350A>G	p.Lys117Arg	missense_variant	Exon 2 of 19	ENST00000680143.1	NP_001354800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBRSL1	ENST00000680143.1	c.350A>G	p.Lys117Arg	missense_variant	Exon 2 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.350A>G	p.Lys117Arg	missense_variant	Exon 2 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.350A>G	p.Lys117Arg	missense_variant	Exon 2 of 20			ENSP00000496901.1
FBRSL1	ENST00000542061.2	c.53A>G	p.Lys18Arg	missense_variant	Exon 3 of 4	2		ENSP00000490180.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 34

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000655 AC: 1 AN: 152556 AF XY: 0.0000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 40 AN: 1398896 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 18 AN XY: 689950

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000361 AC: 39 AN: 1078928

Other (OTH) AF: 0.0000172 AC: 1 AN: 57992

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.350A>G (p.K117R) alteration is located in exon 2 (coding exon 2) of the FBRSL1 gene. This alteration results from a A to G substitution at nucleotide position 350, causing the lysine (K) at amino acid position 117 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	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0066	T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
PhyloP100		0.14
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;.;.
REVEL	Benign	0.036
Sift	Benign	0.053	T;.;.
Sift4G	Benign	0.072	T;.;.
Polyphen		0.99	D;.;.
Vest4		0.19
MutPred		0.22		Loss of methylation at K117 (P = 0.0085);Loss of methylation at K117 (P = 0.0085);.;
MVP		0.040
ClinPred		0.72	D
GERP RS		4.3
Varity_R		0.070
gMVP		0.22
Mutation Taster		=97/3	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: rs1223506294; hg19: chr12-133084797;