rs782721874

Variant names:

• chrX-154371181-T-TCGA
• rs782721874
• NM_001110556.2:c.62_64dupTCG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):​c.62_64dupTCG​(p.Val21dup) variant causes a conservative 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 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.43
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia

  Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• frontometaphyseal dysplasia 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• heterotopia, periventricular, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Melnick-Needles syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• terminal osseous dysplasia-pigmentary defects syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cardiac valvular dysplasia, X-linked

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital short bowel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• otopalatodigital syndrome type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Ehlers-Danlos syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 57 XL,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.62_64dupTCG	p.Val21dup	conservative_inframe_insertion	Exon 2 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.62_64dupTCG	p.Val21dup	conservative_inframe_insertion	Exon 2 of 47	NP_001447.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.62_64dupTCG	p.Val21dup	conservative_inframe_insertion	Exon 2 of 48	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.62_64dupTCG	p.Val21dup	conservative_inframe_insertion	Exon 1 of 46	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.-20_-18dupTCG		5_prime_UTR	Exon 1 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 144 AN: 112358 Hom.: 0 Cov.: 25

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

GnomAD2 exomes AF: 0.00158 AC: 230 AN: 145796 AF XY: 0.00138

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 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

African (AFR) AF: 0.000229 AC: 6 AN: 26209

American (AMR) AF: 0.0000305 AC: 1 AN: 32819

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19020

East Asian (EAS) AF: 0.00 AC: 0 AN: 29604

South Asian (SAS) AF: 0.000269 AC: 14 AN: 52094

European-Finnish (FIN) AF: 0.00895 AC: 342 AN: 38205

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3764

European-Non Finnish (NFE) AF: 0.00121 AC: 1010 AN: 834653

Other (OTH) AF: 0.000595 AC: 27 AN: 45380

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

African (AFR) AF: 0.000161 AC: 5 AN: 31012

American (AMR) AF: 0.00 AC: 0 AN: 10841

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2704

European-Finnish (FIN) AF: 0.00938 AC: 58 AN: 6185

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00151 AC: 80 AN: 53064

Other (OTH) AF: 0.000654 AC: 1 AN: 1528

Alfa AF: 0.00113 Hom.: 9

Bravo AF: 0.000631

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=88/12	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs782721874; hg19: chrX-153599549; COSMIC: COSV61049867;