Genetic Variant NM_005892.4:c.1534A>G (chr17-45241583-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005892.4(FMNL1):c.1534A>G(p.Ser512Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,558,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FMNL1
NM_005892.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.218

Variant links:

Genes affected

FMNL1 (HGNC:1212): (formin like 1) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

FMNL1 links:

FMNL1-AS1 (HGNC:55717): (FMNL1 antisense RNA 1)

FMNL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010804921).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4 link	c.1534A>G	p.Ser512Gly	missense_variant	Exon 14 of 27	ENST00000331495.8	NP_005883.3	O95466-1
FMNL1	NM_001411128.1 link	c.1534A>G	p.Ser512Gly	missense_variant	Exon 14 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1 link	n.188T>C		non_coding_transcript_exon_variant	Exon 1 of 2
FMNL1-AS1	NR_186808.1 link	n.188T>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FMNL1	ENST00000331495.8 link	c.1534A>G	p.Ser512Gly	missense_variant	Exon 14 of 27	1	NM_005892.4	ENSP00000329219.2	O95466-1
FMNL1	ENST00000587489.6 link	c.1534A>G	p.Ser512Gly	missense_variant	Exon 14 of 26	1		ENSP00000465474.2	O95466-2K7EK60
FMNL1-AS1	ENST00000587534.1 link	n.152T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
FMNL1	ENST00000587856.1 link	n.1891A>G		non_coding_transcript_exon_variant	Exon 7 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

170952

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

93212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000739

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

175

AN:

1406226

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

694398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000784

Gnomad4 ASJ exome

AF:

0.00311

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.000345

GnomAD4 genome

AF:

0.000118

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.000104

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1534A>G (p.S512G) alteration is located in exon 14 (coding exon 14) of the FMNL1 gene. This alteration results from a A to G substitution at nucleotide position 1534, causing the serine (S) at amino acid position 512 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.022

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

N;.;.

REVEL

Benign

0.13

Sift

Benign

0.26

T;.;.

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.10

MVP

0.60

MPC

0.53

ClinPred

0.019

GERP RS

0.078

Varity_R

0.075

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over