NM_001110556.2:c.1813G>A

Variant names:

• chrX-154364836-C-T
• rs201093148
• NM_001110556.2:c.1813G>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.1813G>A​(p.Asp605Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000251 in 1,209,926 control chromosomes in the GnomAD database, including 1 homozygotes. There are 112 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D605D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 65 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (1 hom. 47 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.87
• Publications: 7 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 (MetaRNN=0.008234531).
• BP6: Variant X-154364836-C-T is Benign according to our data. Variant chrX-154364836-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00125 (140/112143) while in subpopulation AMR AF = 0.0127 (135/10663). AF 95% confidence interval is 0.0109. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 65 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.1813G>A	p.Asp605Asn	missense	Exon 12 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.1813G>A	p.Asp605Asn	missense	Exon 12 of 47	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.1813G>A	p.Asp605Asn	missense	Exon 12 of 48	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.1813G>A	p.Asp605Asn	missense	Exon 11 of 46	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.1732G>A	p.Asp578Asn	missense	Exon 11 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 140 AN: 112089 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

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: 0.0000188

Gnomad OTH AF: 0.000657

GnomAD2 exomes AF: 0.000661 AC: 120 AN: 181568 AF XY: 0.000563

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00416

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: 0.00112

GnomAD4 exome AF: 0.000149 AC: 164 AN: 1097783 Hom.: 1 Cov.: 33 AF XY: 0.000129 AC XY: 47 AN XY: 363377

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00429 AC: 151 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 842122

Other (OTH) AF: 0.000174 AC: 8 AN: 46092

GnomAD4 genome AF: 0.00125 AC: 140 AN: 112143 Hom.: 0 Cov.: 24 AF XY: 0.00189 AC XY: 65 AN XY: 34317

African (AFR) AF: 0.0000972 AC: 3 AN: 30867

American (AMR) AF: 0.0127 AC: 135 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6231

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53053

Other (OTH) AF: 0.000649 AC: 1 AN: 1540

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00155

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.058	T
Sift4G	Benign	0.53	T
Polyphen		0.024	B
Vest4		0.22
MVP		0.89
MPC		0.60
ClinPred		0.036	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.67
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201093148; hg19: chrX-153593204; COSMIC: COSV61046408;