rs200278701

Variant names:

• chrX-154366214-C-T
• rs200278701
• NM_001110556.2:c.1239G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001110556.2(FLNA):​c.1239G>A​(p.Thr413Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,209,541 control chromosomes in the GnomAD database, including 1 homozygotes. There are 76 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (1 hom., 30 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 46 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -5.08
• Publications: 1 publications found

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

FLNA Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia

  Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• frontometaphyseal dysplasia 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• heterotopia, periventricular, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Melnick-Needles syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• terminal osseous dysplasia-pigmentary defects syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cardiac valvular dysplasia, X-linked

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital short bowel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• otopalatodigital syndrome type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Ehlers-Danlos syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-154366214-C-T is Benign according to our data. Variant chrX-154366214-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129059.
• BP7: Synonymous conserved (PhyloP=-5.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000925 (104/112440) while in subpopulation AFR AF = 0.00294 (91/30997). AF 95% confidence interval is 0.00245. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 30 XL,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110556.2. 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
	FLNA	NM_001110556.2	MANE Select	c.1239G>A	p.Thr413Thr	synonymous	Exon 9 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.1239G>A	p.Thr413Thr	synonymous	Exon 9 of 47	NP_001447.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.1239G>A	p.Thr413Thr	synonymous	Exon 9 of 48	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.1239G>A	p.Thr413Thr	synonymous	Exon 8 of 46	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.1158G>A	p.Thr386Thr	synonymous	Exon 8 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes AF: 0.000925 AC: 104 AN: 112386 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.000372 AC: 67 AN: 180134 AF XY: 0.000360

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000260

Gnomad NFE exome AF: 0.0000248

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000134 AC: 147 AN: 1097101 Hom.: 0 Cov.: 33 AF XY: 0.000127 AC XY: 46 AN XY: 362977

African (AFR) AF: 0.00330 AC: 87 AN: 26400

American (AMR) AF: 0.000454 AC: 16 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54140

European-Finnish (FIN) AF: 0.000304 AC: 12 AN: 39508

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4130

European-Non Finnish (NFE) AF: 0.0000261 AC: 22 AN: 842055

Other (OTH) AF: 0.000195 AC: 9 AN: 46079

GnomAD4 genome AF: 0.000925 AC: 104 AN: 112440 Hom.: 1 Cov.: 24 AF XY: 0.000867 AC XY: 30 AN XY: 34616

African (AFR) AF: 0.00294 AC: 91 AN: 30997

American (AMR) AF: 0.000279 AC: 3 AN: 10762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000942 AC: 5 AN: 53089

Other (OTH) AF: 0.00262 AC: 4 AN: 1527

Alfa AF: 0.000498 Hom.: 1

Bravo AF: 0.00117

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.76
DANN	Benign	0.63
PhyloP100		-5.1
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs200278701; hg19: chrX-153594582;