rs199853721

Variant names:

• chrX-154366598-G-A
• rs199853721
• NM_001110556.2:c.1029C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154366598-G-A
• chrX-154366598-G-C

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.1029C>T​(p.Ser343Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,210,788 control chromosomes in the GnomAD database, including 3 homozygotes. There are 571 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 0.0011 (1 hom., 32 hem., cov: 25)
  • Exomes 𝑓: 0.0016 (2 hom. 539 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -1.69
• Publications: 2 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

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

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

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

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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: Unknown 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=-0.58).
• BP6: Variant X-154366598-G-A is Benign according to our data. Variant chrX-154366598-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198468.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (124/112909) while in subpopulation NFE AF = 0.00199 (106/53236). AF 95% confidence interval is 0.00168. There are 1 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 32 XL,AD,AR,Unknown 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.1029C>T	p.Ser343Ser	synonymous	Exon 7 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.1029C>T	p.Ser343Ser	synonymous	Exon 7 of 47	NP_001447.2	P21333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.1029C>T	p.Ser343Ser	synonymous	Exon 7 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.1029C>T	p.Ser343Ser	synonymous	Exon 6 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.948C>T	p.Ser316Ser	synonymous	Exon 6 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 124 AN: 112856 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.000370

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.000920 AC: 167 AN: 181600 AF XY: 0.000961

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.0000738

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.00157 AC: 1727 AN: 1097879 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 539 AN XY: 363263

African (AFR) AF: 0.000265 AC: 7 AN: 26398

American (AMR) AF: 0.000994 AC: 35 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.000774 AC: 15 AN: 19383

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.0000742 AC: 3 AN: 40454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00192 AC: 1614 AN: 841871

Other (OTH) AF: 0.00111 AC: 51 AN: 46085

GnomAD4 genome AF: 0.00110 AC: 124 AN: 112909 Hom.: 1 Cov.: 25 AF XY: 0.000913 AC XY: 32 AN XY: 35055

African (AFR) AF: 0.000257 AC: 8 AN: 31115

American (AMR) AF: 0.000370 AC: 4 AN: 10812

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6289

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00199 AC: 106 AN: 53236

Other (OTH) AF: 0.00194 AC: 3 AN: 1548

Alfa AF: 0.000982 Hom.: 7

Bravo AF: 0.00111

EpiCase AF: 0.00104

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not specified (6)
-	-	5	not provided (5)
-	-	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	-0.58
CADD	Benign	2.7
DANN	Benign	0.55
PhyloP100		-1.7
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199853721; hg19: chrX-153594966; COSMIC: COSV100774203; COSMIC: COSV100774203;