12-132490836-G-T

Variant names:

• chr12-132490836-G-T
• rs1430685011
• NM_001367871.1:c.266G>T

Variant summary

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

The NM_001367871.1(FBRSL1):​c.266G>T​(p.Ser89Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000791 in 1,263,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S89T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.22
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.266G>T	p.Ser89Ile	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.266G>T	p.Ser89Ile	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.266G>T	p.Ser89Ile	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.266G>T	p.Ser89Ile	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.91e-7 AC: 1 AN: 1263992 Hom.: 0 Cov.: 36 AF XY: 0.00000160 AC XY: 1 AN XY: 623058

African (AFR) AF: 0.0000394 AC: 1 AN: 25372

American (AMR) AF: 0.00 AC: 0 AN: 22032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21240

East Asian (EAS) AF: 0.00 AC: 0 AN: 26692

South Asian (SAS) AF: 0.00 AC: 0 AN: 65162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1012250

Other (OTH) AF: 0.00 AC: 0 AN: 50664

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		8.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.84	P;.
Vest4		0.66
MutPred		0.34		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.17
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.49
Mutation Taster		=65/35	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: rs1430685011; hg19: chr12-133067422;