rs61741041

Variant names:

• chrX-154357459-C-T
• rs61741041
• NM_001110556.2:c.4920G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001110556.2(FLNA):​c.4920G>A​(p.Gly1640Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,208,249 control chromosomes in the GnomAD database, including 1,634 homozygotes. There are 4,745 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (811 hom., 2321 hem., cov: 24)
  • Exomes 𝑓: 0.0083 (823 hom. 2424 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.75
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-154357459-C-T is Benign according to our data. Variant chrX-154357459-C-T is described in ClinVar as Benign. ClinVar VariationId is 93763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 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.4920G>A	p.Gly1640Gly	synonymous	Exon 29 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.4920G>A	p.Gly1640Gly	synonymous	Exon 29 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.4920G>A	p.Gly1640Gly	synonymous	Exon 29 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.4920G>A	p.Gly1640Gly	synonymous	Exon 28 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.4839G>A	p.Gly1613Gly	synonymous	Exon 28 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.0752 AC: 8490 AN: 112953 Hom.: 811 Cov.: 24

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.000938

Gnomad OTH AF: 0.0655

GnomAD2 exomes AF: 0.0211 AC: 3775 AN: 178854 AF XY: 0.0141

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.000136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000752

Gnomad OTH exome AF: 0.00934

GnomAD4 exome AF: 0.00833 AC: 9122 AN: 1095245 Hom.: 823 Cov.: 32 AF XY: 0.00671 AC XY: 2424 AN XY: 361251

African (AFR) AF: 0.280 AC: 7370 AN: 26347

American (AMR) AF: 0.0149 AC: 524 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.000207 AC: 4 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30130

South Asian (SAS) AF: 0.000758 AC: 41 AN: 54068

European-Finnish (FIN) AF: 0.0000249 AC: 1 AN: 40159

Middle Eastern (MID) AF: 0.0117 AC: 48 AN: 4120

European-Non Finnish (NFE) AF: 0.000363 AC: 305 AN: 839982

Other (OTH) AF: 0.0180 AC: 829 AN: 45952

GnomAD4 genome AF: 0.0753 AC: 8508 AN: 113004 Hom.: 811 Cov.: 24 AF XY: 0.0660 AC XY: 2321 AN XY: 35176

African (AFR) AF: 0.258 AC: 8006 AN: 30975

American (AMR) AF: 0.0318 AC: 345 AN: 10833

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.00106 AC: 3 AN: 2831

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6356

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.000938 AC: 50 AN: 53319

Other (OTH) AF: 0.0647 AC: 100 AN: 1546

Alfa AF: 0.0658 Hom.: 372

Bravo AF: 0.0877

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.0
DANN	Benign	0.82
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=78/22	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: rs61741041; hg19: chrX-153585827;