chrX-154358492-C-G

Position:

• chrX-154358492-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001110556.2(FLNA):​c.4551G>C​(p.Gly1517=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,208,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 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 0.000045 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00011 (0 hom. 50 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.45

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-154358492-C-G is Benign according to our data. Variant chrX-154358492-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 289609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.4551G>C	p.Gly1517=	synonymous_variant	27/48	ENST00000369850.10
FLNA	NM_001456.4	c.4551G>C	p.Gly1517=	synonymous_variant	27/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.4551G>C	p.Gly1517=	synonymous_variant	27/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 6 AN: 111724 Hom.: 0 Cov.: 24 AF XY: 0.0000885 AC XY: 3 AN XY: 33886

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000994 AC: 18 AN: 181177 Hom.: 0 AF XY: 0.000163 AC XY: 11 AN XY: 67447

Gnomad AFR exome AF: 0.0000810

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 121 AN: 1096758 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 50 AN XY: 362288

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111776 Hom.: 0 Cov.: 24 AF XY: 0.0000884 AC XY: 3 AN XY: 33948

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000755

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 2

Bravo AF: 0.0000567

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	FLNA: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 29, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2019

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.1
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs370476531; hg19: chrX-153586860;