rs368399445

chrX-154354918-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001110556.2(FLNA):c.5124C>T(p.Phe1708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 1,211,035 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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 0.000062 (0 hom., 1 hem., cov: 26)
  • Exomes 𝑓: 0.00010 (0 hom. 30 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-154354918-G-A is Benign according to our data. Variant chrX-154354918-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.5124C>T	p.Phe1708=	synonymous_variant	31/48	ENST00000369850.10
FLNA	NM_001456.4	c.5100C>T	p.Phe1700=	synonymous_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.5124C>T	p.Phe1708=	synonymous_variant	31/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000618 AC: 7 AN: 113283 Hom.: 0 Cov.: 26 AF XY: 0.0000282 AC XY: 1 AN XY: 35423

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000920

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000165 AC: 3 AN: 181390 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 111 AN: 1097752 Hom.: 0 Cov.: 32 AF XY: 0.0000826 AC XY: 30 AN XY: 363348

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000618 AC: 7 AN: 113283 Hom.: 0 Cov.: 26 AF XY: 0.0000282 AC XY: 1 AN XY: 35423

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000920

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	1.1
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs368399445; hg19: chrX-153583286; COSMIC: COSV100775239; COSMIC: COSV100775239;