rs3817579

Variant names:

• chr2-201351096-T-C
• rs3817579
• NM_001127391.3:c.113+196A>G

Variant summary

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

The NM_001127391.3(FLACC1):​c.113+196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0607 in 152,226 control chromosomes in the GnomAD database, including 583 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 0.061 (583 hom., cov: 32)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.113+196A>G		intron_variant	Intron 2 of 14	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.113+196A>G		intron_variant	Intron 2 of 14	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 9210 AN: 152106 Hom.: 580 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0617

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0607 AC: 9238 AN: 152226 Hom.: 583 Cov.: 32 AF XY: 0.0639 AC XY: 4759 AN XY: 74428

African (AFR) AF: 0.121 AC: 5030 AN: 41532

American (AMR) AF: 0.0317 AC: 484 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1279 AN: 5162

South Asian (SAS) AF: 0.192 AC: 928 AN: 4822

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10604

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1109 AN: 68024

Other (OTH) AF: 0.0634 AC: 134 AN: 2114

Alfa AF: 0.0343 Hom.: 706

Bravo AF: 0.0624

Asia WGS AF: 0.224 AC: 778 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.67
DANN	Benign	0.48
PhyloP100		-1.2
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3817579; hg19: chr2-202215819;