rs200053635

Variant names:

• chrX-154362534-G-A
• rs200053635
• NM_001110556.2:c.2449C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001110556.2(FLNA):​c.2449C>T​(p.Pro817Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,210,103 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 200 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). Synonymous variant affecting the same amino acid position (i.e. P817P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 11 hem., cov: 24)
  • Exomes 𝑓: 0.00046 (0 hom. 189 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12 O:1
• Conservation: PhyloP100: 3.46
• Publications: 6 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0738256).
• BP6: Variant X-154362534-G-A is Benign according to our data. Variant chrX-154362534-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194727.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000311 (35/112721) while in subpopulation SAS AF = 0.0018 (5/2780). AF 95% confidence interval is 0.000708. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 11 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.2449C>T	p.Pro817Ser	missense	Exon 17 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.2449C>T	p.Pro817Ser	missense	Exon 17 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.2449C>T	p.Pro817Ser	missense	Exon 17 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.2449C>T	p.Pro817Ser	missense	Exon 16 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.2368C>T	p.Pro790Ser	missense	Exon 16 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.000311 AC: 35 AN: 112721 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000933

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000454 AC: 82 AN: 180748 AF XY: 0.000610

Gnomad AFR exome AF: 0.0000809

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000251

Gnomad NFE exome AF: 0.000745

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000460 AC: 505 AN: 1097382 Hom.: 0 Cov.: 33 AF XY: 0.000520 AC XY: 189 AN XY: 363178

African (AFR) AF: 0.0000379 AC: 1 AN: 26401

American (AMR) AF: 0.0000284 AC: 1 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 3 AN: 19386

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

South Asian (SAS) AF: 0.000886 AC: 48 AN: 54146

European-Finnish (FIN) AF: 0.000100 AC: 4 AN: 39840

Middle Eastern (MID) AF: 0.000968 AC: 4 AN: 4134

European-Non Finnish (NFE) AF: 0.000504 AC: 424 AN: 841989

Other (OTH) AF: 0.000434 AC: 20 AN: 46075

GnomAD4 genome AF: 0.000311 AC: 35 AN: 112721 Hom.: 0 Cov.: 24 AF XY: 0.000315 AC XY: 11 AN XY: 34873

African (AFR) AF: 0.00 AC: 0 AN: 31040

American (AMR) AF: 0.0000933 AC: 1 AN: 10723

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00180 AC: 5 AN: 2780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000545 AC: 29 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.000556 Hom.: 30

Bravo AF: 0.000200

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000305 AC: 2

ExAC AF: 0.000545 AC: 66

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	1	-	Disorder of sexual differentiation (1)
-	1	-	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FLNA-related disorder (2)
-	-	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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.074	T
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.11
MVP		0.86
MPC		0.68
ClinPred		0.088	T
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.51
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: rs200053635; hg19: chrX-153590902;