12-6555283-C-G

Position:

• chr12-6555283-C-G

Variant summary

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

The NM_001193457.2(IFFO1):​c.747G>C​(p.Lys249Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFFO1 NM_001193457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

Genes affected

IFFO1 (HGNC:24970): (intermediate filament family orphan 1) This gene is a member of the intermediate filament family. Intermediate filaments are proteins which are primordial components of the cytoskeleton and nuclear envelope. The proteins encoded by the members of this gene family are evolutionarily and structurally related but have limited sequence homology, with the exception of the central rod domain. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFFO1	NM_001193457.2	c.747G>C	p.Lys249Asn	missense_variant	1/10	ENST00000619571.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFFO1	ENST00000619571.5	c.747G>C	p.Lys249Asn	missense_variant	1/10	2	NM_001193457.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.747G>C (p.K249N) alteration is located in exon 1 (coding exon 1) of the IFFO1 gene. This alteration results from a G to C substitution at nucleotide position 747, causing the lysine (K) at amino acid position 249 to be replaced by an asparagine (N). 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	Pathogenic	1.0
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.3	L;L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.52
Sift	Benign	0.058	T;T;.;T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.52
MutPred		0.57		Loss of methylation at K249 (P = 0.002);Loss of methylation at K249 (P = 0.002);Loss of methylation at K249 (P = 0.002);Loss of methylation at K249 (P = 0.002);
MVP		0.83
MPC		0.65
ClinPred		0.90	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.80

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: rs1367081405; hg19: chr12-6664449;