rs36051194

Variant names:

• chrX-154366167-G-A
• rs36051194
• NM_001110556.2:c.1286C>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_001110556.2(FLNA):​c.1286C>T​(p.Thr429Met) variant causes a missense change. The variant allele was found at a frequency of 0.0169 in 1,209,111 control chromosomes in the GnomAD database, including 168 homozygotes. There are 6,589 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T429T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (12 hom., 608 hem., cov: 24)
  • Exomes 𝑓: 0.017 (156 hom. 5981 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.01
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008827686).
• BP6: Variant X-154366167-G-A is Benign according to our data. Variant chrX-154366167-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93748.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 = 0.0143 (1607/112464) while in subpopulation NFE AF = 0.018 (953/53083). AF 95% confidence interval is 0.017. There are 12 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.1286C>T	p.Thr429Met	missense	Exon 9 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.1286C>T	p.Thr429Met	missense	Exon 9 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.1286C>T	p.Thr429Met	missense	Exon 9 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.1286C>T	p.Thr429Met	missense	Exon 8 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.1205C>T	p.Thr402Met	missense	Exon 8 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1608 AN: 112411 Hom.: 12 Cov.: 24

Gnomad AFR AF: 0.00252

Gnomad AMI AF: 0.0248

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0151 AC: 2724 AN: 180120 AF XY: 0.0145

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.0000739

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0172 AC: 18849 AN: 1096647 Hom.: 156 Cov.: 33 AF XY: 0.0165 AC XY: 5981 AN XY: 362695

African (AFR) AF: 0.00220 AC: 58 AN: 26395

American (AMR) AF: 0.00454 AC: 160 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 211 AN: 19379

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.000480 AC: 26 AN: 54143

European-Finnish (FIN) AF: 0.0585 AC: 2294 AN: 39187

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4124

European-Non Finnish (NFE) AF: 0.0183 AC: 15438 AN: 841940

Other (OTH) AF: 0.0142 AC: 656 AN: 46071

GnomAD4 genome AF: 0.0143 AC: 1607 AN: 112464 Hom.: 12 Cov.: 24 AF XY: 0.0175 AC XY: 608 AN XY: 34688

African (AFR) AF: 0.00251 AC: 78 AN: 31032

American (AMR) AF: 0.0104 AC: 112 AN: 10773

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 30 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2755

European-Finnish (FIN) AF: 0.0645 AC: 399 AN: 6185

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

European-Non Finnish (NFE) AF: 0.0180 AC: 953 AN: 53083

Other (OTH) AF: 0.0118 AC: 18 AN: 1530

Alfa AF: 0.0159 Hom.: 800

Bravo AF: 0.0108

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0204 AC: 59

ESP6500AA AF: 0.00246 AC: 9

ESP6500EA AF: 0.0163 AC: 107

ExAC AF: 0.0153 AC: 1856

EpiCase AF: 0.0172

EpiControl AF: 0.0145

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FLNA-related disorder (1)
-	-	1	Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1 (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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.58
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.44
MPC		1.2
ClinPred		0.030	T
GERP RS		3.8
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36051194; hg19: chrX-153594535;