NM_001110556.2:c.5616G>C

Variant names:

• chrX-154353985-C-G
• rs782204300
• NM_001110556.2:c.5616G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP6_Very_Strong BP7 BS2

The NM_001110556.2(FLNA):​c.5616G>C​(p.Gly1872Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,210,244 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1872G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.000074 (0 hom. 30 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.57
• 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 -13 ACMG points.

• BP6: Variant X-154353985-C-G is Benign according to our data. Variant chrX-154353985-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 30 XL,AD,AR 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.5616G>C	p.Gly1872Gly	synonymous	Exon 35 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.5592G>C	p.Gly1864Gly	synonymous	Exon 34 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.5616G>C	p.Gly1872Gly	synonymous	Exon 35 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.5592G>C	p.Gly1864Gly	synonymous	Exon 33 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.5535G>C	p.Gly1845Gly	synonymous	Exon 34 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.0000532 AC: 6 AN: 112771 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000386 AC: 7 AN: 181510 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000738 AC: 81 AN: 1097473 Hom.: 0 Cov.: 32 AF XY: 0.0000827 AC XY: 30 AN XY: 362901

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000939 AC: 79 AN: 841555

Other (OTH) AF: 0.0000217 AC: 1 AN: 46070

GnomAD4 genome AF: 0.0000532 AC: 6 AN: 112771 Hom.: 0 Cov.: 25 AF XY: 0.0000286 AC XY: 1 AN XY: 34941

African (AFR) AF: 0.0000644 AC: 2 AN: 31058

American (AMR) AF: 0.00 AC: 0 AN: 10745

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.79
CADD	Benign	5.9
DANN	Benign	0.54
PhyloP100		-1.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=97/3	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: rs782204300; hg19: chrX-153582353;