rs12721503

Variant names:

• chr2-201163219-T-C
• rs12721503
• ENST00000457277.5:c.*139T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000457277.5(CFLAR):​c.*139T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,271,616 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (58 hom., cov: 32)
  • Exomes 𝑓: 0.020 (290 hom.)
• Consequence: CFLAR ENST00000457277.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0179 (2722/152304) while in subpopulation SAS AF = 0.0267 (129/4828). AF 95% confidence interval is 0.023. There are 58 homozygotes in GnomAd4. There are 1474 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2722 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000457277.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFLAR	NM_003879.7	MANE Select	c.1305-616T>C		intron	N/A	NP_003870.4
	CFLAR	NR_147243.2		n.1702T>C		non_coding_transcript_exon	Exon 10 of 11
	CFLAR	NR_147244.2		n.1702T>C		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFLAR	ENST00000457277.5	TSL:1	c.*139T>C		3_prime_UTR	Exon 9 of 9	ENSP00000411535.1
	CFLAR	ENST00000309955.8	TSL:1 MANE Select	c.1305-616T>C		intron	N/A	ENSP00000312455.2
	CFLAR	ENST00000423241.6	TSL:1	c.1305-616T>C		intron	N/A	ENSP00000399420.2

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2721 AN: 152186 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0198 AC: 22160 AN: 1119312 Hom.: 290 Cov.: 14 AF XY: 0.0200 AC XY: 10846 AN XY: 541396

African (AFR) AF: 0.00362 AC: 90 AN: 24892

American (AMR) AF: 0.0128 AC: 165 AN: 12858

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 698 AN: 16196

East Asian (EAS) AF: 0.000894 AC: 27 AN: 30212

South Asian (SAS) AF: 0.0279 AC: 1246 AN: 44600

European-Finnish (FIN) AF: 0.0765 AC: 1864 AN: 24360

Middle Eastern (MID) AF: 0.0256 AC: 119 AN: 4652

European-Non Finnish (NFE) AF: 0.0185 AC: 16967 AN: 915454

Other (OTH) AF: 0.0214 AC: 984 AN: 46088

GnomAD4 genome AF: 0.0179 AC: 2722 AN: 152304 Hom.: 58 Cov.: 32 AF XY: 0.0198 AC XY: 1474 AN XY: 74468

African (AFR) AF: 0.00397 AC: 165 AN: 41570

American (AMR) AF: 0.0136 AC: 208 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5194

South Asian (SAS) AF: 0.0267 AC: 129 AN: 4828

European-Finnish (FIN) AF: 0.0719 AC: 763 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1257 AN: 68020

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.0187 Hom.: 13

Bravo AF: 0.0134

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.9
DANN	Benign	0.77
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs12721503; hg19: chr2-202027942;