X-154358194-C-T

Variant names:

• chrX-154358194-C-T
• rs199803218
• NM_001110556.2:c.4755+5G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BS1 BS2

The NM_001110556.2(FLNA):​c.4755+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000529 in 1,208,782 control chromosomes in the GnomAD database, including 4 homozygotes. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000057 (4 hom. 12 hem.)
• Consequence: FLNA NM_001110556.2 splice_region, intron
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.84
• 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, 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 -9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant X-154358194-C-T is Benign according to our data. Variant chrX-154358194-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 464996.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000575 (63/1096251) while in subpopulation EAS AF = 0.00209 (63/30191). AF 95% confidence interval is 0.00167. There are 4 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.4755+5G>A		splice_region_variant, intron_variant	Intron 28 of 47	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.4755+5G>A		splice_region_variant, intron_variant	Intron 28 of 46		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.4755+5G>A		splice_region_variant, intron_variant	Intron 28 of 47	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112478 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000567 AC: 10 AN: 176504 AF XY: 0.0000308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000743

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 63 AN: 1096251 Hom.: 4 Cov.: 32 AF XY: 0.0000331 AC XY: 12 AN XY: 362513

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00209 AC: 63 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3966

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841665

Other (OTH) AF: 0.00 AC: 0 AN: 46014

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112531 Hom.: 0 Cov.: 24 AF XY: 0.0000288 AC XY: 1 AN XY: 34685

African (AFR) AF: 0.00 AC: 0 AN: 31037

American (AMR) AF: 0.00 AC: 0 AN: 10768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53133

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Benign:1

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	21
DANN	Benign	0.51
PhyloP100		5.8
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.020		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: rs199803218; hg19: chrX-153586562;