12-132490616-G-C

Variant names:

• chr12-132490616-G-C
• rs949454511
• NM_001367871.1:c.46G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367871.1(FBRSL1):​c.46G>C​(p.Asp16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 837,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D16N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3446512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.46G>C	p.Asp16His	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.46G>C	p.Asp16His	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.46G>C	p.Asp16His	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.46G>C	p.Asp16His	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000358 AC: 3 AN: 837230 Hom.: 0 Cov.: 28 AF XY: 0.00000517 AC XY: 2 AN XY: 387142

African (AFR) AF: 0.00 AC: 0 AN: 15818

American (AMR) AF: 0.00 AC: 0 AN: 1108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5232

East Asian (EAS) AF: 0.00 AC: 0 AN: 3724

South Asian (SAS) AF: 0.00 AC: 0 AN: 17322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1632

European-Non Finnish (NFE) AF: 0.00000392 AC: 3 AN: 764424

Other (OTH) AF: 0.00 AC: 0 AN: 27464

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0067	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		3.1
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.028	D;.
Polyphen		1.0	D;.
Vest4		0.11
MutPred		0.32		Gain of methylation at R19 (P = 0.0474);Gain of methylation at R19 (P = 0.0474);
MVP		0.11
ClinPred		0.64	D
GERP RS		3.4
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.30
Mutation Taster		=84/16	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: rs949454511; hg19: chr12-133067202;