12-49890715-A-G

Variant names:

• chr12-49890715-A-G
• NM_012306.4:c.493T>C

Variant summary

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

The NM_012306.4(FAIM2):​c.493T>C​(p.Phe165Leu) variant causes a missense change involving the alteration of a 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: FAIM2 NM_012306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

Genes affected

FAIM2 (HGNC:17067): (Fas apoptotic inhibitory molecule 2) Involved in regulation of neuron apoptotic process. Acts upstream of or within negative regulation of extrinsic apoptotic signaling pathway via death domain receptors. Located in membrane raft. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
FAIM2	NM_012306.4	c.493T>C	p.Phe165Leu	missense_variant	Exon 7 of 12	ENST00000320634.8	NP_036438.2
FAIM2	XM_005268730.4	c.367T>C	p.Phe123Leu	missense_variant	Exon 6 of 11		XP_005268787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAIM2	ENST00000320634.8	c.493T>C	p.Phe165Leu	missense_variant	Exon 7 of 12	1	NM_012306.4	ENSP00000321951.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493T>C (p.F165L) alteration is located in exon 7 (coding exon 7) of the FAIM2 gene. This alteration results from a T to C substitution at nucleotide position 493, causing the phenylalanine (F) at amino acid position 165 to be replaced by a leucine (L). 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	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.036	D;T;T;D
Sift4G	Benign	0.11	T;T;T;.
Polyphen		0.85	P;.;.;.
Vest4		0.56
MutPred		0.51		Gain of catalytic residue at F165 (P = 0);.;.;Gain of catalytic residue at F165 (P = 0);
MVP		0.35
MPC		0.92
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr12-50284498;