NM_001127391.3:c.676-7274G>A

Variant names:

• chr2-201316524-C-T
• rs1830298
• NM_001127391.3:c.676-7274G>A

Variant summary

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

The NM_001127391.3(FLACC1):​c.676-7274G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 151,918 control chromosomes in the GnomAD database, including 39,783 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 (39783 hom., cov: 30)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 35 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=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.676-7274G>A		intron_variant	Intron 9 of 14	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.676-7274G>A		intron_variant	Intron 9 of 14	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109361 AN: 151800 Hom.: 39744 Cov.: 30

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.677

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

GnomAD4 genome AF: 0.720 AC: 109447 AN: 151918 Hom.: 39783 Cov.: 30 AF XY: 0.717 AC XY: 53242 AN XY: 74250

African (AFR) AF: 0.786 AC: 32586 AN: 41452

American (AMR) AF: 0.576 AC: 8782 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2165 AN: 3466

East Asian (EAS) AF: 0.697 AC: 3605 AN: 5172

South Asian (SAS) AF: 0.829 AC: 3984 AN: 4808

European-Finnish (FIN) AF: 0.666 AC: 7019 AN: 10540

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

European-Non Finnish (NFE) AF: 0.721 AC: 48972 AN: 67918

Other (OTH) AF: 0.678 AC: 1431 AN: 2112

Alfa AF: 0.731 Hom.: 5027

Bravo AF: 0.713

Asia WGS AF: 0.788 AC: 2740 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.52
DANN	Benign	0.34
PhyloP100		-1.0
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: rs1830298; hg19: chr2-202181247;