NM_001110556.2:c.2023-8C>T

Variant names:

• chrX-154364380-G-A
• rs587780335
• NM_001110556.2:c.2023-8C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001110556.2(FLNA):​c.2023-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,092,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000061 (0 hom. 17 hem.)
• Consequence: FLNA NM_001110556.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001867
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.957
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae), Illumina
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Melnick-Needles syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• terminal osseous dysplasia-pigmentary defects syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, 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: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-154364380-G-A is Benign according to our data. Variant chrX-154364380-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129061.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000613 (67/1092352) while in subpopulation AMR AF = 0.00173 (61/35202). AF 95% confidence interval is 0.00138. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 17 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.2023-8C>T		splice_region intron	N/A	NP_001104026.1
	FLNA	NM_001456.4		c.2023-8C>T		splice_region intron	N/A	NP_001447.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.2023-8C>T		splice_region intron	N/A	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.2023-8C>T		splice_region intron	N/A	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.1942-8C>T		splice_region intron	N/A	ENSP00000358872.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.000287 AC: 52 AN: 181132 AF XY: 0.000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000613 AC: 67 AN: 1092352 Hom.: 0 Cov.: 32 AF XY: 0.0000475 AC XY: 17 AN XY: 358212

African (AFR) AF: 0.00 AC: 0 AN: 26291

American (AMR) AF: 0.00173 AC: 61 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 53996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3975

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 837548

Other (OTH) AF: 0.0000436 AC: 2 AN: 45895

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	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	-0.81
CADD	Benign	5.4
DANN	Benign	0.55
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs587780335; hg19: chrX-153592748;