15-68290074-T-C

Position:

• chr15-68290074-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015322.5(FEM1B):​c.716T>C​(p.Leu239Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FEM1B NM_015322.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

Genes affected

FEM1B (HGNC:3649): (fem-1 homolog B) This gene encodes an ankyrin repeat protein that belongs to the death receptor-associated family of proteins and plays a role in mediating apoptosis. The encoded protein is also thought to function in the replication stress-induced checkpoint signaling pathway via interaction with checkpoint kinase 1. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FEM1B	NM_015322.5	c.716T>C	p.Leu239Pro	missense_variant	2/2	ENST00000306917.5	NP_056137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FEM1B	ENST00000306917.5	c.716T>C	p.Leu239Pro	missense_variant	2/2	1	NM_015322.5	ENSP00000307298.4
FEM1B	ENST00000566739.1	c.*1T>C		downstream_gene_variant		4		ENSP00000457342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.85		Gain of disorder (P = 0.0376);
MVP		0.92
MPC		2.6
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-68582412;