rs201093148

Positions:

• chrX-154364836-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):​c.1813G>A​(p.Asp605Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000251 in 1,209,926 control chromosomes in the GnomAD database, including 1 homozygotes. There are 112 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D605D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 65 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (1 hom. 47 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.87

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.008234531).
• BP6: Variant X-154364836-C-T is Benign according to our data. Variant chrX-154364836-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00125 (140/112143) while in subpopulation AMR AF= 0.0127 (135/10663). AF 95% confidence interval is 0.0109. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 65 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1813G>A	p.Asp605Asn	missense_variant	12/48	ENST00000369850.10
FLNA	NM_001456.4	c.1813G>A	p.Asp605Asn	missense_variant	12/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1813G>A	p.Asp605Asn	missense_variant	12/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 140 AN: 112089 Hom.: 0 Cov.: 24 AF XY: 0.00190 AC XY: 65 AN XY: 34253

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

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: 0.0000188

Gnomad OTH AF: 0.000657

GnomAD3 exomes AF: 0.000661 AC: 120 AN: 181568 Hom.: 1 AF XY: 0.000563 AC XY: 38 AN XY: 67510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00416

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: 0.0000123

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000149 AC: 164 AN: 1097783 Hom.: 1 Cov.: 33 AF XY: 0.000129 AC XY: 47 AN XY: 363377

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00429

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: 0.00000594

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.00125 AC: 140 AN: 112143 Hom.: 0 Cov.: 24 AF XY: 0.00189 AC XY: 65 AN XY: 34317

Gnomad4 AFR AF: 0.0000972

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000649

Bravo AF: 0.00155

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 12, 2018	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2018

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D;.;.;.;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D;D;.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.3	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N;.;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.058	T;.;T;T;.
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.024	B;.;B;B;.
Vest4		0.22
MVP		0.89
MPC		0.60
ClinPred		0.036	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201093148; hg19: chrX-153593204; COSMIC: COSV61046408;