rs1557178374

chrX-154362756-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_001110556.2(FLNA):c.2309A>G(p.Asn770Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,089,139 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N770K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.1955083).
• BP6: Variant X-154362756-T-C is Benign according to our data. Variant chrX-154362756-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 488377.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.2309A>G	p.Asn770Ser	missense_variant	16/48	ENST00000369850.10
FLNA	NM_001456.4	c.2309A>G	p.Asn770Ser	missense_variant	16/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.2309A>G	p.Asn770Ser	missense_variant	16/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000367 AC: 4 AN: 1089139 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 356261

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000477

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Oto-palato-digital syndrome, type I Benign:1

Likely benign, no assertion criteria provided

research

Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School

Oct 27, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Benign	0.60
DEOGEN2	Benign	0.41	T;.;.;.;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.37	N;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;.;N;N;.
REVEL	Benign	0.29
Sift	Benign	0.92	T;.;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.015	B;.;B;B;.
Vest4		0.15
MutPred		0.33		Gain of disorder (P = 0.0578);.;Gain of disorder (P = 0.0578);Gain of disorder (P = 0.0578);.;
MVP		0.79
MPC		0.44
ClinPred		0.35	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557178374; hg19: chrX-153591124;