2-201133056-T-A

Position:

• chr2-201133056-T-A

Variant summary

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

The NM_003879.7(CFLAR):​c.309T>A​(p.Asp103Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFLAR NM_003879.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.215

Genes affected

CFLAR (HGNC:1876): (CASP8 and FADD like apoptosis regulator) The protein encoded by this gene is a regulator of apoptosis and is structurally similar to caspase-8. However, the encoded protein lacks caspase activity and appears to be itself cleaved into two peptides by caspase-8. Several transcript variants encoding different isoforms have been found for this gene, and partial evidence for several more variants exists. [provided by RefSeq, Feb 2011]

CFLAR (HGNC:):

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=0.13067868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.309T>A	p.Asp103Glu	missense_variant	3/10	ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.309T>A	p.Asp103Glu	missense_variant	3/10	1	NM_003879.7	ENSP00000312455.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

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

Aug 05, 2024

The c.309T>A (p.D103E) alteration is located in exon 3 (coding exon 2) of the CFLAR gene. This alteration results from a T to A substitution at nucleotide position 309, causing the aspartic acid (D) at amino acid position 103 to be replaced by a glutamic acid (E). 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	0.20
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.8
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T;.;.;.;.;.;T;T;.;.;.;T;T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.80	.;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.98	L;.;L;L;L;.;.;L;.;L;L;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.20	T;D;T;D;T;T;T;T;T;T;T;.;.;.;.;.
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.43	B;.;B;P;B;B;.;B;.;B;P;.;.;.;B;.
Vest4		0.067
MutPred		0.43		Gain of disorder (P = 0.1731);.;Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);Gain of disorder (P = 0.1731);.;.;.;.;.;
MVP		0.66
MPC		1.2
ClinPred		0.20	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.21

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: chr2-201997779;