Genetic Variant FITM1:p.Ala19Val (chr14-24131619-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203402.3(FITM1):c.56C>T(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,610,636 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

FITM1
NM_203402.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.492

Variant links:

Genes affected

FITM1 (HGNC:33714): (fat storage inducing transmembrane protein 1) Predicted to enable diacylglycerol binding activity and triglyceride binding activity. Predicted to be involved in lipid droplet formation; phospholipid biosynthetic process; and positive regulation of sequestering of triglyceride. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

FITM1 links:

ENSG00000259371 (HGNC:):

ENSG00000259371 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01075986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FITM1	NM_203402.3 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 2	ENST00000267426.6	NP_981947.1	A5D6W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FITM1	ENST00000267426.6 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 2	1	NM_203402.3	ENSP00000267426.5		A5D6W6-1
ENSG00000259371	ENST00000558325.2 link	c.638C>T	p.Ala213Val	missense_variant	Exon 4 of 4	5		ENSP00000453089.2		H0YL77

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000529

AC:

129

AN:

244002

Hom.:

AF XY:

0.000482

AC XY:

AN XY:

132744

show subpopulations

Gnomad AFR exome

AF:

0.0000642

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.000910

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000610

AC:

889

AN:

1458312

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

446

AN XY:

725166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00135

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000152

Gnomad4 NFE exome

AF:

0.000726

Gnomad4 OTH exome

AF:

0.000415

GnomAD4 genome

AF:

0.000479

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000723

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.000772

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.A19V) alteration is located in exon 1 (coding exon 1) of the FITM1 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.043

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.045

M_CAP

Benign

0.0067

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.0

REVEL

Benign

0.014

Sift

Benign

0.20

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.12

MVP

0.22

MPC

0.17

ClinPred

0.014

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.043

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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