NM_001367871.1:c.46G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001367871.1(FBRSL1):​c.46G>A​(p.Asp16Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 983,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: FBRSL1 NM_001367871.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26497674).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1	c.46G>A	p.Asp16Asn	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>A	p.Asp16Asn	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1
FBRSL1	ENST00000434748.2	c.46G>A	p.Asp16Asn	missense_variant	Exon 1 of 17	1		ENSP00000396160.2
FBRSL1	ENST00000650108.1	c.46G>A	p.Asp16Asn	missense_variant	Exon 1 of 20			ENSP00000496901.1

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000491

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 20 AN: 837230 Hom.: 0 Cov.: 28 AF XY: 0.0000258 AC XY: 10 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: 0.0000235 AC: 18 AN: 764424

Other (OTH) AF: 0.0000728 AC: 2 AN: 27464

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146154 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 1 AN XY: 71072

African (AFR) AF: 0.0000491 AC: 2 AN: 40770

American (AMR) AF: 0.00 AC: 0 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65794

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>A (p.D16N) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the aspartic acid (D) at amino acid position 16 to be replaced by an asparagine (N). 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.0048	T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		3.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.11
Sift	Benign	0.12	T;.
Sift4G	Benign	0.14	T;.
Polyphen		0.99	D;.
Vest4		0.10
MutPred		0.25		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.048
ClinPred		0.51	D
GERP RS		3.4
PromoterAI		0.16	Neutral
Varity_R		0.15
gMVP		0.17
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;