rs700635

Variant names:

• chr2-201288502-C-A
• rs700635
• NM_001127391.3:c.*153G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127391.3(FLACC1):​c.*153G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 891,274 control chromosomes in the GnomAD database, including 233,103 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 0.72 (39818 hom., cov: 31)
  • Exomes 𝑓: 0.72 (193285 hom.)
• Consequence: FLACC1 NM_001127391.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.792
• Publications: 34 publications found

Genes affected

FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.*153G>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.*153G>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109449 AN: 151930 Hom.: 39779 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.678

GnomAD4 exome AF: 0.721 AC: 533233 AN: 739226 Hom.: 193285 Cov.: 10 AF XY: 0.724 AC XY: 269662 AN XY: 372542

African (AFR) AF: 0.782 AC: 14090 AN: 18022

American (AMR) AF: 0.549 AC: 11190 AN: 20400

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 8984 AN: 14502

East Asian (EAS) AF: 0.680 AC: 22465 AN: 33034

South Asian (SAS) AF: 0.824 AC: 33039 AN: 40076

European-Finnish (FIN) AF: 0.675 AC: 21059 AN: 31214

Middle Eastern (MID) AF: 0.668 AC: 2642 AN: 3956

European-Non Finnish (NFE) AF: 0.727 AC: 395002 AN: 543166

Other (OTH) AF: 0.710 AC: 24762 AN: 34856

GnomAD4 genome AF: 0.720 AC: 109535 AN: 152048 Hom.: 39818 Cov.: 31 AF XY: 0.717 AC XY: 53268 AN XY: 74302

African (AFR) AF: 0.786 AC: 32616 AN: 41476

American (AMR) AF: 0.576 AC: 8785 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2167 AN: 3470

East Asian (EAS) AF: 0.698 AC: 3594 AN: 5150

South Asian (SAS) AF: 0.827 AC: 3997 AN: 4834

European-Finnish (FIN) AF: 0.665 AC: 7016 AN: 10552

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49025 AN: 67998

Other (OTH) AF: 0.679 AC: 1429 AN: 2106

Alfa AF: 0.718 Hom.: 93743

Bravo AF: 0.713

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	6.0
DANN	Benign	0.33
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs700635; hg19: chr2-202153225; COSMIC: COSV109406641; COSMIC: COSV109406641;