NM_002024.6:c.433G>T

Variant names:

• chrX-147929961-G-T
• rs29281
• NM_002024.6:c.433G>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.433G>T​(p.Ala145Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 1,191,575 control chromosomes in the GnomAD database, including 192 homozygotes. There are 1,528 hemizygotes 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (103 hom., 727 hem., cov: 22)
  • Exomes 𝑓: 0.0029 (89 hom. 801 hem.)
• Consequence: FMR1 NM_002024.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.97
• Publications: 8 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=0.0017594695).
• BP6: Variant X-147929961-G-T is Benign according to our data. Variant chrX-147929961-G-T is described in ClinVar as Benign. ClinVar VariationId is 129104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 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.433G>T	p.Ala145Ser	missense	Exon 6 of 17	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.433G>T	p.Ala145Ser	missense	Exon 6 of 16	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.433G>T	p.Ala145Ser	missense	Exon 6 of 16	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.433G>T	p.Ala145Ser	missense	Exon 6 of 17	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.433G>T	p.Ala145Ser	missense	Exon 6 of 16	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.433G>T	p.Ala145Ser	missense	Exon 6 of 16	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 2820 AN: 110893 Hom.: 103 Cov.: 22

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00931

Gnomad ASJ AF: 0.000758

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.000506

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.0188

GnomAD2 exomes AF: 0.00772 AC: 1396 AN: 180837 AF XY: 0.00445

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000503

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00289 AC: 3122 AN: 1080631 Hom.: 89 Cov.: 28 AF XY: 0.00230 AC XY: 801 AN XY: 348921

African (AFR) AF: 0.0893 AC: 2321 AN: 25997

American (AMR) AF: 0.00610 AC: 214 AN: 35075

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 29 AN: 19269

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30119

South Asian (SAS) AF: 0.000392 AC: 21 AN: 53510

European-Finnish (FIN) AF: 0.000741 AC: 30 AN: 40463

Middle Eastern (MID) AF: 0.00229 AC: 9 AN: 3931

European-Non Finnish (NFE) AF: 0.000243 AC: 201 AN: 826805

Other (OTH) AF: 0.00651 AC: 296 AN: 45462

GnomAD4 genome AF: 0.0255 AC: 2826 AN: 110944 Hom.: 103 Cov.: 22 AF XY: 0.0219 AC XY: 727 AN XY: 33264

African (AFR) AF: 0.0882 AC: 2682 AN: 30406

American (AMR) AF: 0.00930 AC: 97 AN: 10432

Ashkenazi Jewish (ASJ) AF: 0.000758 AC: 2 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2661

European-Finnish (FIN) AF: 0.000506 AC: 3 AN: 5930

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.000208 AC: 11 AN: 52918

Other (OTH) AF: 0.0186 AC: 28 AN: 1507

Alfa AF: 0.0110 Hom.: 398

Bravo AF: 0.0303

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0920 AC: 353

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.00850 AC: 1032

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Fragile X syndrome (1)
-	-	1	Fragile X syndrome;C1839780:Fragile X-associated tremor/ataxia syndrome;C4552079:Premature ovarian failure 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.15
DEOGEN2	Benign	0.0050	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		5.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.62
MPC		0.81
ClinPred		0.0020	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.31
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: rs29281; hg19: chrX-147011480; COSMIC: COSV54425690; COSMIC: COSV54425690;