chrX-154359317-G-A

Variant names:

• chrX-154359317-G-A
• rs782426283
• NM_001110556.2:c.4232C>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.4232C>T​(p.Ser1411Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,209,922 control chromosomes in the GnomAD database, including 1 homozygotes. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1411S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (1 hom. 120 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 1.16
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038050085).
• BP6: Variant X-154359317-G-A is Benign according to our data. Variant chrX-154359317-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435207.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000621 (7/112702) while in subpopulation SAS AF = 0.00108 (3/2788). AF 95% confidence interval is 0.000292. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.4232C>T	p.Ser1411Leu	missense	Exon 25 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.4232C>T	p.Ser1411Leu	missense	Exon 25 of 47	NP_001447.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	ENST00000369850.10	TSL:1 MANE Select	c.4232C>T	p.Ser1411Leu	missense	Exon 25 of 48	ENSP00000358866.3
	FLNA	ENST00000360319.9	TSL:1	c.4232C>T	p.Ser1411Leu	missense	Exon 24 of 46	ENSP00000353467.4
	FLNA	ENST00000369856.8	TSL:1	c.4151C>T	p.Ser1384Leu	missense	Exon 24 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes AF: 0.0000621 AC: 7 AN: 112702 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000359 AC: 65 AN: 181241 AF XY: 0.000460

Gnomad AFR exome AF: 0.0000809

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000213 AC: 234 AN: 1097220 Hom.: 1 Cov.: 33 AF XY: 0.000330 AC XY: 120 AN XY: 363132

African (AFR) AF: 0.0000758 AC: 2 AN: 26398

American (AMR) AF: 0.0000284 AC: 1 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00392 AC: 212 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39661

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 842004

Other (OTH) AF: 0.000195 AC: 9 AN: 46083

GnomAD4 genome AF: 0.0000621 AC: 7 AN: 112702 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 5 AN XY: 34848

African (AFR) AF: 0.0000967 AC: 3 AN: 31035

American (AMR) AF: 0.00 AC: 0 AN: 10744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00108 AC: 3 AN: 2788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53223

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000298 Hom.: 1

Bravo AF: 0.0000945

ExAC AF: 0.000487 AC: 59

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.038	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.95	P
Vest4		0.24
MutPred		0.53		Gain of catalytic residue at S1411 (P = 0.0016)
MVP		0.90
MPC		0.68
ClinPred		0.095	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.69
Mutation Taster		=85/15	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: rs782426283; hg19: chrX-153587685;