rs782721874

chrX-154371181-T-TCGA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):c.64_65insTCG(p.Val21dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,194,156 control chromosomes in the GnomAD database, including 1 homozygotes. There are 488 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D22D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 57 hem., cov: 25)
  • Exomes 𝑓: 0.0013 (1 hom. 431 hem.)
• Consequence: FLNA NM_001110556.2 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.43

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.

• PM4: Nonframeshift variant in NON repetitive region in NM_001110556.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-154371181-T-TCGA is Benign according to our data. Variant chrX-154371181-T-TCGA is described in ClinVar as [Likely_benign]. Clinvar id is 213457.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 = 0.00128 (144/112408) while in subpopulation NFE AF= 0.00151 (80/53064). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.64_65insTCG	p.Val21dup	inframe_insertion	2/48	ENST00000369850.10
FLNA	NM_001456.4	c.64_65insTCG	p.Val21dup	inframe_insertion	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.64_65insTCG	p.Val21dup	inframe_insertion	2/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 144 AN: 112358 Hom.: 0 Cov.: 25 AF XY: 0.00165 AC XY: 57 AN XY: 34568

Gnomad AFR AF: 0.000162

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: 0.00938

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.00158 AC: 230 AN: 145796 Hom.: 0 AF XY: 0.00138 AC XY: 64 AN XY: 46318

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.0000833

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000248

Gnomad FIN exome AF: 0.00928

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00129 AC: 1400 AN: 1081748 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 431 AN XY: 352672

Gnomad4 AFR exome AF: 0.000229

Gnomad4 AMR exome AF: 0.0000305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000269

Gnomad4 FIN exome AF: 0.00895

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000595

GnomAD4 genome AF: 0.00128 AC: 144 AN: 112408 Hom.: 0 Cov.: 25 AF XY: 0.00165 AC XY: 57 AN XY: 34630

Gnomad4 AFR AF: 0.000161

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00938

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00113 Hom.: 9

Bravo AF: 0.000631

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	FLNA: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2020	This variant is associated with the following publications: (PMID: 29334594) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2017

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

Feb 01, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782721874; hg19: chrX-153599549;