chr12-132490740-C-T

Variant names:

• chr12-132490740-C-T
• rs748463485
• NM_001367871.1:c.170C>T

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.170C>T​(p.Ala57Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,008,998 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A57T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• 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=0.10875133).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.170C>T	p.Ala57Val	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.170C>T	p.Ala57Val	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.170C>T	p.Ala57Val	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.170C>T	p.Ala57Val	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes AF: 0.0000683 AC: 10 AN: 146510 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 588 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 29 AN: 862488 Hom.: 0 Cov.: 28 AF XY: 0.0000274 AC XY: 11 AN XY: 400806

African (AFR) AF: 0.00 AC: 0 AN: 16362

American (AMR) AF: 0.00 AC: 0 AN: 1638

Ashkenazi Jewish (ASJ) AF: 0.00281 AC: 16 AN: 5684

East Asian (EAS) AF: 0.00 AC: 0 AN: 5600

South Asian (SAS) AF: 0.00 AC: 0 AN: 17404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1686

European-Non Finnish (NFE) AF: 0.0000115 AC: 9 AN: 782576

Other (OTH) AF: 0.000138 AC: 4 AN: 28918

GnomAD4 genome AF: 0.0000683 AC: 10 AN: 146510 Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 5 AN XY: 71260

African (AFR) AF: 0.00 AC: 0 AN: 40808

American (AMR) AF: 0.00 AC: 0 AN: 14752

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 10 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65956

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000616 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.170C>T (p.A57V) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a C to T substitution at nucleotide position 170, causing the alanine (A) at amino acid position 57 to be replaced by a valine (V). 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	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0032	T;.
Eigen	Benign	0.091
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.38	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.66	N;.
REVEL	Benign	0.064
Sift	Benign	0.13	T;.
Sift4G	Benign	0.15	T;.
Polyphen		0.99	D;.
Vest4		0.066
MutPred		0.25		Gain of MoRF binding (P = 0.081);Gain of MoRF binding (P = 0.081);
MVP		0.040
ClinPred		0.76	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.081
gMVP		0.093
Mutation Taster		=87/13	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: rs748463485; hg19: chr12-133067326;