rs398123615

Variant names:

• chrX-154361368-G-A
• rs398123615
• NM_001110556.2:c.3147C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154361368-G-A
• chrX-154361368-G-C
• chrX-154361368-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001110556.2(FLNA):​c.3147C>T​(p.Gly1049Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,207,882 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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. G1049G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 8 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.82
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-154361368-G-A is Benign according to our data. Variant chrX-154361368-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93754.
• BP7: Synonymous conserved (PhyloP=-3.82 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 8 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.3147C>T	p.Gly1049Gly	synonymous	Exon 21 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.3147C>T	p.Gly1049Gly	synonymous	Exon 21 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.3147C>T	p.Gly1049Gly	synonymous	Exon 21 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.3147C>T	p.Gly1049Gly	synonymous	Exon 20 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.3066C>T	p.Gly1022Gly	synonymous	Exon 20 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110711 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000379

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000332 AC: 6 AN: 180889 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

Gnomad FIN exome AF: 0.0000629

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000355 AC: 39 AN: 1097171 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 8 AN XY: 362955

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30203

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54141

European-Finnish (FIN) AF: 0.0000251 AC: 1 AN: 39838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000356 AC: 30 AN: 841800

Other (OTH) AF: 0.0000217 AC: 1 AN: 46073

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110711 Hom.: 0 Cov.: 22 AF XY: 0.0000304 AC XY: 1 AN XY: 32919

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.00 AC: 0 AN: 10391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2639

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5929

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52795

Other (OTH) AF: 0.00 AC: 0 AN: 1474

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.14
DANN	Benign	0.49
PhyloP100		-3.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=84/16	polymorphism

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: rs398123615; hg19: chrX-153589736; COSMIC: COSV105910624;