12-132490731-C-A

Variant names:

• chr12-132490731-C-A
• NM_001367871.1:c.161C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367871.1(FBRSL1):​c.161C>A​(p.Pro54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 844,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. P54R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

Genes affected

FBRSL1 (HGNC:29308): (fibrosin like 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25137854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.161C>A	p.Pro54His	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.161C>A	p.Pro54His	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.161C>A	p.Pro54His	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.161C>A	p.Pro54His	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000237 AC: 2 AN: 844496 Hom.: 0 Cov.: 28 AF XY: 0.00000256 AC XY: 1 AN XY: 391372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000260

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161C>A (p.P54H) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a C to A substitution at nucleotide position 161, causing the proline (P) at amino acid position 54 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	0.065
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.28	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.052
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.021	D;.
Polyphen		1.0	D;.
Vest4		0.17
MutPred		0.19		Loss of catalytic residue at P53 (P = 0.0144);Loss of catalytic residue at P53 (P = 0.0144);
MVP		0.25
ClinPred		0.64	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.19

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133067317;