dbSNP rs145567470: CFLAR:p.Asp118Glu (chr2-201133101-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003879.7(CFLAR):c.354T>G(p.Asp118Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Consequence

CFLAR
NM_003879.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.815

Publications

0 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFLAR	NM_003879.7 link	c.354T>G	p.Asp118Glu	missense_variant	Exon 3 of 10	ENST00000309955.8	NP_003870.4	O15519-1A0A024R3Y4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8 link	c.354T>G	p.Asp118Glu	missense_variant	Exon 3 of 10	1	NM_003879.7	ENSP00000312455.2		O15519-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251462

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.354T>G (p.D118E) alteration is located in exon 3 (coding exon 2) of the CFLAR gene. This alteration results from a T to G substitution at nucleotide position 354, causing the aspartic acid (D) at amino acid position 118 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

Uncertain

0.44

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;.;.;.;.;T;T;.;.;.;T;T;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.91

.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;D;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.5

M;.;M;M;M;.;.;M;.;M;M;.;.;.;.;.

PhyloP100

0.81

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N;N;N;N;.;.;.;.;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.021

D;D;D;D;D;T;D;D;D;D;D;.;.;.;.;.

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;D;D;D;.;D;.;D;D;.;.;.;D;.

Vest4

0.32

MutPred

0.60

Loss of ubiquitination at K117 (P = 0.0949);.;Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);Loss of ubiquitination at K117 (P = 0.0949);.;.;.;.;.;

MVP

0.89

MPC

2.5

ClinPred

0.94

GERP RS

2.5

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.36

Mutation Taster

=88/12

polymorphism

(source)

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

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rs145567470

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over