14-24132362-C-G

Variant names:

• chr14-24132362-C-G
• NM_203402.3:c.418C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203402.3(FITM1):​c.418C>G​(p.Arg140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,522 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FITM1 NM_203402.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.172

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16281128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FITM1	NM_203402.3	c.418C>G	p.Arg140Gly	missense_variant	Exon 2 of 2	ENST00000267426.6	NP_981947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FITM1	ENST00000267426.6	c.418C>G	p.Arg140Gly	missense_variant	Exon 2 of 2	1	NM_203402.3	ENSP00000267426.5
FITM1	ENST00000559294	c.-171C>G		5_prime_UTR_variant	Exon 1 of 1			ENSP00000453741.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418C>G (p.R140G) alteration is located in exon 2 (coding exon 2) of the FITM1 gene. This alteration results from a C to G substitution at nucleotide position 418, causing the arginine (R) at amino acid position 140 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	0.11
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.34	T
Sift4G	Benign	0.41	T
Polyphen		0.74	P
Vest4		0.20
MutPred		0.45		Gain of catalytic residue at A138 (P = 0);
MVP		0.37
MPC		0.23
ClinPred		0.54	D
GERP RS		1.2
Varity_R		0.19
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24601571;