Genetic Variant FLNA:c.*88C>T (chrX-154348761-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.28

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 196 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.*88C>T		3_prime_UTR_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.*88C>T		3_prime_UTR_variant	Exon 47 of 47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850 link	c.*88C>T		3_prime_UTR_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

685

AN:

102877

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

196

AN XY:

28661

show subpopulations

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.:

Cov.:

AF XY:

0.00894

AC XY:

1851

AN XY:

207103

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00128

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.0000388

Gnomad4 SAS exome

AF:

0.00199

Gnomad4 FIN exome

AF:

0.00689

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00668

GnomAD4 genome

AF:

0.00666

AC:

685

AN:

102882

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

196

AN XY:

28686

show subpopulations

Gnomad4 AFR

AF:

0.00146

Gnomad4 AMR

AF:

0.000920

Gnomad4 ASJ

AF:

0.0249

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.00214

Alfa

AF:

0.00594

Hom.:

Bravo

AF:

0.00526

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over