rs782265090

Positions:

• chrX-147930136-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002024.6(FMR1):​c.522T>A​(p.Asn174Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,198,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 79 hem.)
• Consequence: FMR1 NM_002024.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

Genes affected

FMR1 (HGNC:3775): (fragile X messenger ribonucleoprotein 1) The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016963959).
• BP6: Variant X-147930136-T-A is Benign according to our data. Variant chrX-147930136-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 211029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000448 (5/111610) while in subpopulation SAS AF= 0.00187 (5/2672). AF 95% confidence interval is 0.000737. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMR1	NM_002024.6	c.522T>A	p.Asn174Lys	missense_variant	7/17	ENST00000370475.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMR1	ENST00000370475.9	c.522T>A	p.Asn174Lys	missense_variant	7/17	1	NM_002024.6	P3

Frequencies

GnomAD3 genomes AF: 0.0000448 AC: 5 AN: 111610 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33804

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 43 AN: 183260 Hom.: 0 AF XY: 0.000487 AC XY: 33 AN XY: 67768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 115 AN: 1086605 Hom.: 0 Cov.: 29 AF XY: 0.000224 AC XY: 79 AN XY: 352711

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: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000601

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.0000448 AC: 5 AN: 111610 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33804

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T;.;.;.;.;T;T;.;T;T;T;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.53, 0.088, 0.13, 0.040	.;.;.;P;.;B;B;B;B;.;.;.
Vest4		0.46
MutPred		0.35		Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);.;Gain of ubiquitination at N174 (P = 0.0219);
MVP		0.73
MPC		1.1
ClinPred		0.091	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782265090; hg19: chrX-147011655;