rs2070825

Variant names:

• chrX-154353564-A-G
• rs2070825
• NM_001110556.2:c.5850T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001110556.2(FLNA):​c.5850T>C​(p.Ala1950Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,209,033 control chromosomes in the GnomAD database, including 11,142 homozygotes. There are 54,049 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3218 hom., 7419 hem., cov: 25)
  • Exomes 𝑓: 0.13 (7924 hom. 46630 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.47
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-154353564-A-G is Benign according to our data. Variant chrX-154353564-A-G is described in ClinVar as Benign. ClinVar VariationId is 93766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

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.5850T>C	p.Ala1950Ala	synonymous	Exon 36 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.5826T>C	p.Ala1942Ala	synonymous	Exon 35 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.5850T>C	p.Ala1950Ala	synonymous	Exon 36 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.5826T>C	p.Ala1942Ala	synonymous	Exon 34 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.5769T>C	p.Ala1923Ala	synonymous	Exon 35 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.223 AC: 24965 AN: 112013 Hom.: 3205 Cov.: 25

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0588

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.155 AC: 28172 AN: 181171 AF XY: 0.146

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.0735

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.129 AC: 141332 AN: 1096966 Hom.: 7924 Cov.: 33 AF XY: 0.129 AC XY: 46630 AN XY: 362626

African (AFR) AF: 0.503 AC: 13268 AN: 26387

American (AMR) AF: 0.202 AC: 7097 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1139 AN: 19381

East Asian (EAS) AF: 0.108 AC: 3268 AN: 30181

South Asian (SAS) AF: 0.201 AC: 10871 AN: 54127

European-Finnish (FIN) AF: 0.142 AC: 5696 AN: 40088

Middle Eastern (MID) AF: 0.0777 AC: 321 AN: 4130

European-Non Finnish (NFE) AF: 0.111 AC: 93025 AN: 841457

Other (OTH) AF: 0.144 AC: 6647 AN: 46049

GnomAD4 genome AF: 0.223 AC: 25028 AN: 112067 Hom.: 3218 Cov.: 25 AF XY: 0.216 AC XY: 7419 AN XY: 34309

African (AFR) AF: 0.492 AC: 15117 AN: 30715

American (AMR) AF: 0.187 AC: 2009 AN: 10730

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 148 AN: 2643

East Asian (EAS) AF: 0.0925 AC: 329 AN: 3558

South Asian (SAS) AF: 0.209 AC: 574 AN: 2748

European-Finnish (FIN) AF: 0.134 AC: 829 AN: 6166

Middle Eastern (MID) AF: 0.0599 AC: 13 AN: 217

European-Non Finnish (NFE) AF: 0.107 AC: 5690 AN: 53064

Other (OTH) AF: 0.205 AC: 316 AN: 1540

Alfa AF: 0.143 Hom.: 3888

Bravo AF: 0.240

EpiCase AF: 0.102

EpiControl AF: 0.0903

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	not provided (2)
-	-	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	-0.65
CADD	Benign	8.6
DANN	Benign	0.58
PhyloP100		2.5
PromoterAI		-0.0070	Neutral
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: rs2070825; hg19: chrX-153581932; COSMIC: COSV61039995; COSMIC: COSV61039995;