X-147936627-C-T

Variant names:

• chrX-147936627-C-T
• rs25714
• NM_002024.6:c.990+14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002024.6(FMR1):​c.990+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,016,839 control chromosomes in the GnomAD database, including 8,332 homozygotes. There are 32,742 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1085 hom., 3999 hem., cov: 23)
  • Exomes 𝑓: 0.10 (7247 hom. 28743 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.190
• Publications: 16 publications found

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]

FMR1 Gene-Disease associations (from GenCC):

• fragile X syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Myriad Women’s Health, G2P
• fragile X-associated tremor/ataxia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• premature ovarian failure 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• symptomatic form of fragile X syndrome in female carrier

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-147936627-C-T is Benign according to our data. Variant chrX-147936627-C-T is described in ClinVar as Benign. ClinVar VariationId is 94025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002024.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.990+14C>T		intron	N/A	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.990+14C>T		intron	N/A	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.990+14C>T		intron	N/A	NP_001172011.1	Q06787-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.990+14C>T		intron	N/A	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.990+14C>T		intron	N/A	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.984+14C>T		intron	N/A	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.121 AC: 13402 AN: 110776 Hom.: 1088 Cov.: 23

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0678

Gnomad NFE AF: 0.0674

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.161 AC: 29106 AN: 181043 AF XY: 0.144

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.714

Gnomad FIN exome AF: 0.0646

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.102 AC: 92357 AN: 906012 Hom.: 7247 Cov.: 18 AF XY: 0.114 AC XY: 28743 AN XY: 253082

African (AFR) AF: 0.126 AC: 2882 AN: 22787

American (AMR) AF: 0.273 AC: 9503 AN: 34850

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 1069 AN: 18157

East Asian (EAS) AF: 0.640 AC: 18821 AN: 29399

South Asian (SAS) AF: 0.140 AC: 6998 AN: 50007

European-Finnish (FIN) AF: 0.0655 AC: 2648 AN: 40405

Middle Eastern (MID) AF: 0.120 AC: 451 AN: 3752

European-Non Finnish (NFE) AF: 0.0673 AC: 44892 AN: 666847

Other (OTH) AF: 0.128 AC: 5093 AN: 39808

GnomAD4 genome AF: 0.121 AC: 13402 AN: 110827 Hom.: 1085 Cov.: 23 AF XY: 0.121 AC XY: 3999 AN XY: 33139

African (AFR) AF: 0.123 AC: 3740 AN: 30459

American (AMR) AF: 0.230 AC: 2403 AN: 10460

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 158 AN: 2636

East Asian (EAS) AF: 0.705 AC: 2456 AN: 3483

South Asian (SAS) AF: 0.145 AC: 386 AN: 2669

European-Finnish (FIN) AF: 0.0544 AC: 321 AN: 5903

Middle Eastern (MID) AF: 0.0657 AC: 14 AN: 213

European-Non Finnish (NFE) AF: 0.0674 AC: 3562 AN: 52816

Other (OTH) AF: 0.157 AC: 236 AN: 1507

Alfa AF: 0.0837 Hom.: 2835

Bravo AF: 0.143

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Fragile X syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs25714; hg19: chrX-147018146; COSMIC: COSV54424142; COSMIC: COSV54424142;