rs202181557

Variant names:

• chrX-154366016-G-A
• rs202181557
• NM_001110556.2:c.1429+8C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154366016-G-A
• chrX-154366016-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001110556.2(FLNA):​c.1429+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,193,254 control chromosomes in the GnomAD database, including 1 homozygotes. There are 774 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 41 hem., cov: 25)
  • Exomes 𝑓: 0.0022 (1 hom. 733 hem.)
• Consequence: FLNA NM_001110556.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004147
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.223
• Publications: 1 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: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• otopalatodigital syndrome type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-154366016-G-A is Benign according to our data. Variant chrX-154366016-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93750.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00155 (175/113100) while in subpopulation NFE AF = 0.00276 (147/53230). AF 95% confidence interval is 0.0024. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 41 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.1429+8C>T		splice_region intron	N/A	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.1429+8C>T		splice_region 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.1429+8C>T		splice_region intron	N/A	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.1429+8C>T		splice_region intron	N/A	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.1348+8C>T		splice_region intron	N/A	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 175 AN: 113043 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.000651

GnomAD2 exomes AF: 0.00109 AC: 184 AN: 168695 AF XY: 0.000965

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00222 AC: 2396 AN: 1080154 Hom.: 1 Cov.: 32 AF XY: 0.00209 AC XY: 733 AN XY: 350854

African (AFR) AF: 0.000344 AC: 9 AN: 26195

American (AMR) AF: 0.000315 AC: 11 AN: 34870

Ashkenazi Jewish (ASJ) AF: 0.0000529 AC: 1 AN: 18906

East Asian (EAS) AF: 0.000100 AC: 3 AN: 29956

South Asian (SAS) AF: 0.000282 AC: 15 AN: 53100

European-Finnish (FIN) AF: 0.00213 AC: 77 AN: 36119

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4049

European-Non Finnish (NFE) AF: 0.00262 AC: 2181 AN: 831572

Other (OTH) AF: 0.00218 AC: 99 AN: 45387

GnomAD4 genome AF: 0.00155 AC: 175 AN: 113100 Hom.: 0 Cov.: 25 AF XY: 0.00116 AC XY: 41 AN XY: 35252

African (AFR) AF: 0.000480 AC: 15 AN: 31254

American (AMR) AF: 0.000277 AC: 3 AN: 10834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2802

European-Finnish (FIN) AF: 0.00143 AC: 9 AN: 6304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00276 AC: 147 AN: 53230

Other (OTH) AF: 0.000644 AC: 1 AN: 1554

Alfa AF: 0.00251 Hom.: 18

Bravo AF: 0.00140

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Heterotopia, periventricular, X-linked dominant (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
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.82
PhyloP100		-0.22
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs202181557;

hg19: chrX-153594384;