X-148003260-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152578.3(FMR1NB):c.337G>A(p.Gly113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,242 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: FMR1NB NM_152578.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

Genes affected

FMR1NB (HGNC:26372): (FMR1 neighbor) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28661102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMR1NB	NM_152578.3	c.337G>A	p.Gly113Ser	missense_variant	2/6	ENST00000370467.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMR1NB	ENST00000370467.8	c.337G>A	p.Gly113Ser	missense_variant	2/6	1	NM_152578.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112242 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34396

Gnomad AFR AF: 0.0000324

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112242 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34396

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.337G>A (p.G113S) alteration is located in exon 2 (coding exon 2) of the FMR1NB gene. This alteration results from a G to A substitution at nucleotide position 337, causing the glycine (G) at amino acid position 113 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.13
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.13
MutPred		0.23		Loss of helix (P = 0.0626);
MVP		0.33
MPC		0.25
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.20
gMVP		0.064

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

LitVar

Other links and lift over

dbSNP: rs1417085116; hg19: chrX-147084780;