2-201160683-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003879.7(CFLAR):​c.1045G>T​(p.Ala349Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

CFLAR
NM_003879.7 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.316
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0804517).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFLARNM_003879.7 linkuse as main transcriptc.1045G>T p.Ala349Ser missense_variant 9/10 ENST00000309955.8 NP_003870.4 O15519-1A0A024R3Y4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFLARENST00000309955.8 linkuse as main transcriptc.1045G>T p.Ala349Ser missense_variant 9/101 NM_003879.7 ENSP00000312455.2 O15519-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152122
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251428
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000759
AC:
111
AN:
1461884
Hom.:
0
Cov.:
36
AF XY:
0.0000743
AC XY:
54
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000998
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152122
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000773
Hom.:
0
Bravo
AF:
0.0000529
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2024The c.1045G>T (p.A349S) alteration is located in exon 9 (coding exon 8) of the CFLAR gene. This alteration results from a G to T substitution at nucleotide position 1045, causing the alanine (A) at amino acid position 349 to be replaced by a serine (S). 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
0.11
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
5.3
DANN
Benign
0.91
DEOGEN2
Benign
0.16
T;.;.;T;.;.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.65
.;T;T;T;T;T;T
M_CAP
Benign
0.0059
T
MetaRNN
Benign
0.080
T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.77
N;.;.;N;N;.;.
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-1.4
N;N;N;N;N;.;.
REVEL
Benign
0.040
Sift
Benign
0.12
T;T;T;T;T;.;.
Sift4G
Benign
0.18
T;T;T;T;T;T;T
Polyphen
0.0010
B;.;B;B;B;B;.
Vest4
0.057
MVP
0.32
MPC
0.28
ClinPred
0.025
T
GERP RS
-2.5
Varity_R
0.12
gMVP
0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143449123; hg19: chr2-202025406; API