rs72616474

Variant names:

• chrX-154353214-G-C
• rs72616474
• NM_001110556.2:c.6023-10C>G

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.6023-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,209,747 control chromosomes in the GnomAD database, including 4 homozygotes. There are 493 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 0.0015 (0 hom., 80 hem., cov: 25)
  • Exomes 𝑓: 0.0012 (4 hom. 413 hem.)
• Consequence: FLNA NM_001110556.2 intron
• Scores: Splicing: ADA: 0.001091
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.649
• Publications: 4 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=-0.8).
• BP6: Variant X-154353214-G-C is Benign according to our data. Variant chrX-154353214-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00148 (167/112589) while in subpopulation EAS AF = 0.0246 (88/3570). AF 95% confidence interval is 0.0205. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 80 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.6023-10C>G		intron	N/A	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.5999-10C>G		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.6023-10C>G		intron	N/A	ENSP00000358866.3	P21333-1
	FLNA	ENST00000360319.9	TSL:1	c.5999-10C>G		intron	N/A	ENSP00000353467.4	P21333-2
	FLNA	ENST00000369856.8	TSL:1	c.5942-10C>G		intron	N/A	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 168 AN: 112535 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.000363

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.000657

GnomAD2 exomes AF: 0.00368 AC: 668 AN: 181586 AF XY: 0.00363

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.0306

Gnomad FIN exome AF: 0.00879

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00119 AC: 1306 AN: 1097158 Hom.: 4 Cov.: 32 AF XY: 0.00114 AC XY: 413 AN XY: 362728

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.000170 AC: 6 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.000206 AC: 4 AN: 19382

East Asian (EAS) AF: 0.0187 AC: 564 AN: 30204

South Asian (SAS) AF: 0.000277 AC: 15 AN: 54129

European-Finnish (FIN) AF: 0.0106 AC: 425 AN: 40165

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4135

European-Non Finnish (NFE) AF: 0.000195 AC: 164 AN: 841487

Other (OTH) AF: 0.00276 AC: 127 AN: 46067

GnomAD4 genome AF: 0.00148 AC: 167 AN: 112589 Hom.: 0 Cov.: 25 AF XY: 0.00230 AC XY: 80 AN XY: 34745

African (AFR) AF: 0.00 AC: 0 AN: 31018

American (AMR) AF: 0.00 AC: 0 AN: 10708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.0246 AC: 88 AN: 3570

South Asian (SAS) AF: 0.000364 AC: 1 AN: 2749

European-Finnish (FIN) AF: 0.0111 AC: 69 AN: 6241

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

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53204

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

Alfa AF: 0.000436 Hom.: 2

Bravo AF: 0.00125

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	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	-0.80
CADD	Benign	15
DANN	Benign	0.49
PhyloP100		0.65
PromoterAI		0.0066	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.080		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: rs72616474; hg19: chrX-153581582; COSMIC: COSV61054032; COSMIC: COSV61054032;