rs143889976

Variant names:

• chrX-147944969-C-T
• rs143889976
• NM_002024.6:c.1572C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001185075.2(FMR1):​c.1301C>T​(p.Ala434Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,204,544 control chromosomes in the GnomAD database, including 4 homozygotes. There are 668 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 39 hem., cov: 22)
  • Exomes 𝑓: 0.0017 (4 hom. 629 hem.)
• Consequence: FMR1 NM_001185075.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.707
• Publications: 2 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, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• fragile X-associated tremor/ataxia syndrome

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

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 (MetaRNN=0.009594232).
• BP6: Variant X-147944969-C-T is Benign according to our data. Variant chrX-147944969-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (128/109560) while in subpopulation NFE AF = 0.00213 (112/52566). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 39 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001185075.2. 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.1572C>T	p.Ser524Ser	synonymous	Exon 15 of 17	NP_002015.1	Q06787-1
	FMR1	NM_001185075.2		c.1301C>T	p.Ala434Val	missense	Exon 14 of 16	NP_001172004.1	Q06787-10
	FMR1	NM_001185081.2		c.1238C>T	p.Ala413Val	missense	Exon 13 of 15	NP_001172010.1	Q06787-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.1572C>T	p.Ser524Ser	synonymous	Exon 15 of 17	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.1509C>T	p.Ser503Ser	synonymous	Exon 14 of 16	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.1503C>T	p.Ser501Ser	synonymous	Exon 14 of 16	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 128 AN: 109507 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000195

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00138

GnomAD2 exomes AF: 0.000983 AC: 172 AN: 175013 AF XY: 0.000880

Gnomad AFR exome AF: 0.0000796

Gnomad AMR exome AF: 0.000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000320

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.00171 AC: 1873 AN: 1094984 Hom.: 4 Cov.: 33 AF XY: 0.00174 AC XY: 629 AN XY: 360620

African (AFR) AF: 0.000341 AC: 9 AN: 26369

American (AMR) AF: 0.000229 AC: 8 AN: 34967

Ashkenazi Jewish (ASJ) AF: 0.0000519 AC: 1 AN: 19282

East Asian (EAS) AF: 0.00 AC: 0 AN: 30158

South Asian (SAS) AF: 0.0000933 AC: 5 AN: 53608

European-Finnish (FIN) AF: 0.000545 AC: 22 AN: 40362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00209 AC: 1760 AN: 840139

Other (OTH) AF: 0.00148 AC: 68 AN: 45970

GnomAD4 genome AF: 0.00117 AC: 128 AN: 109560 Hom.: 0 Cov.: 22 AF XY: 0.00122 AC XY: 39 AN XY: 31896

African (AFR) AF: 0.000266 AC: 8 AN: 30056

American (AMR) AF: 0.000195 AC: 2 AN: 10266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2615

East Asian (EAS) AF: 0.00 AC: 0 AN: 3459

South Asian (SAS) AF: 0.000834 AC: 2 AN: 2397

European-Finnish (FIN) AF: 0.000343 AC: 2 AN: 5831

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00213 AC: 112 AN: 52566

Other (OTH) AF: 0.00136 AC: 2 AN: 1474

Alfa AF: 0.00180 Hom.: 54

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.000981 AC: 119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	FMR1-related disorder (1)
-	-	1	Fragile X syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.82	T
PhyloP100		0.71
PROVEAN	Benign	0.48	N
REVEL	Benign	0.073
Sift	Benign	0.043	D
Sift4G	Benign	0.24	T
Vest4		0.097
MVP		0.97
ClinPred		0.015	T
GERP RS		5.1
Mutation Taster		=99/1	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: rs143889976; hg19: chrX-147026489;