chrX-154348761-G-A

Variant names:

• chrX-154348761-G-A
• rs55760624
• ENST00000490936.5:n.5261C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):​c.*88C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00897 in 855,097 control chromosomes in the GnomAD database, including 35 homozygotes. There are 2,047 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (0 hom., 196 hem., cov: 23)
  • Exomes 𝑓: 0.0093 (35 hom. 1851 hem.)
• Consequence: FLNA NM_001110556.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.28
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-154348761-G-A is Benign according to our data. Variant chrX-154348761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1199805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00666 (685/102882) while in subpopulation NFE AF = 0.0105 (533/50741). AF 95% confidence interval is 0.00977. There are 0 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 196 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2	c.*88C>T		3_prime_UTR_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4	c.*88C>T		3_prime_UTR_variant	Exon 47 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10	c.*88C>T		3_prime_UTR_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 685 AN: 102877 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000921

Gnomad ASJ AF: 0.0249

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.00441

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00214

GnomAD4 exome AF: 0.00928 AC: 6981 AN: 752215 Hom.: 35 Cov.: 13 AF XY: 0.00894 AC XY: 1851 AN XY: 207103

African (AFR) AF: 0.00102 AC: 17 AN: 16717

American (AMR) AF: 0.00128 AC: 26 AN: 20254

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 295 AN: 13603

East Asian (EAS) AF: 0.0000388 AC: 1 AN: 25758

South Asian (SAS) AF: 0.00199 AC: 75 AN: 37605

European-Finnish (FIN) AF: 0.00689 AC: 206 AN: 29884

Middle Eastern (MID) AF: 0.000680 AC: 2 AN: 2940

European-Non Finnish (NFE) AF: 0.0107 AC: 6133 AN: 571627

Other (OTH) AF: 0.00668 AC: 226 AN: 33827

GnomAD4 genome AF: 0.00666 AC: 685 AN: 102882 Hom.: 0 Cov.: 23 AF XY: 0.00683 AC XY: 196 AN XY: 28686

African (AFR) AF: 0.00146 AC: 38 AN: 26095

American (AMR) AF: 0.000920 AC: 9 AN: 9783

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 64 AN: 2575

East Asian (EAS) AF: 0.00 AC: 0 AN: 3437

South Asian (SAS) AF: 0.00167 AC: 4 AN: 2391

European-Finnish (FIN) AF: 0.00593 AC: 33 AN: 5566

Middle Eastern (MID) AF: 0.00485 AC: 1 AN: 206

European-Non Finnish (NFE) AF: 0.0105 AC: 533 AN: 50741

Other (OTH) AF: 0.00214 AC: 3 AN: 1403

Alfa AF: 0.00594 Hom.: 27

Bravo AF: 0.00526

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

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	-0.85
CADD	Benign	0.37
DANN	Benign	0.61
PhyloP100		-3.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	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: rs55760624; hg19: chrX-153577129;