rs201016252

Variant names:

• chrX-154359974-C-T
• rs201016252
• NM_001110556.2:c.3805+16G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154359974-C-T
• chrX-154359974-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110556.2(FLNA):​c.3805+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,203,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 584 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 0.00077 (0 hom., 22 hem., cov: 25)
  • Exomes 𝑓: 0.0017 (0 hom. 562 hem.)
• Consequence: FLNA NM_001110556.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.81
• Publications: 0 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked

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

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

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

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-154359974-C-T is Benign according to our data. Variant chrX-154359974-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213447.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 = 0.000766 (86/112257) while in subpopulation NFE AF = 0.00128 (68/53043). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 22 XL,AD,AR,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.3805+16G>A		intron	N/A	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.3805+16G>A		intron	N/A	NP_001447.2	P21333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.3805+16G>A		intron	N/A	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.3805+16G>A		intron	N/A	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.3724+16G>A		intron	N/A	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.000766 AC: 86 AN: 112205 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000186

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: 0.00128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000551 AC: 99 AN: 179663 AF XY: 0.000403

Gnomad AFR exome AF: 0.000411

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000452

GnomAD4 exome AF: 0.00166 AC: 1815 AN: 1090967 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 562 AN XY: 357383

African (AFR) AF: 0.000228 AC: 6 AN: 26287

American (AMR) AF: 0.000114 AC: 4 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30184

South Asian (SAS) AF: 0.0000555 AC: 3 AN: 54009

European-Finnish (FIN) AF: 0.000101 AC: 4 AN: 39554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00212 AC: 1773 AN: 836390

Other (OTH) AF: 0.000523 AC: 24 AN: 45880

GnomAD4 genome AF: 0.000766 AC: 86 AN: 112257 Hom.: 0 Cov.: 25 AF XY: 0.000639 AC XY: 22 AN XY: 34429

African (AFR) AF: 0.000518 AC: 16 AN: 30914

American (AMR) AF: 0.000186 AC: 2 AN: 10745

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00128 AC: 68 AN: 53043

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000872 Hom.: 7

Bravo AF: 0.000797

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.58
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201016252; hg19: chrX-153588342;