12-108518669-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007076.3(FICD):c.571G>A(p.Asp191Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FICD NM_007076.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

Genes affected

FICD (HGNC:18416): (FIC domain protein adenylyltransferase) Enables several functions, including ATP binding activity; Hsp70 protein binding activity; and chaperone binding activity. Involved in protein adenylylation; regulation of IRE1-mediated unfolded protein response; and response to endoplasmic reticulum stress. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FICD	NM_007076.3	c.571G>A	p.Asp191Asn	missense_variant	3/3	ENST00000552695.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FICD	ENST00000552695.6	c.571G>A	p.Asp191Asn	missense_variant	3/3	1	NM_007076.3	P1
FICD	ENST00000361549.2	c.*308G>A		3_prime_UTR_variant	3/3	1
FICD	ENST00000549641.1	c.153+1396G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.571G>A (p.D191N) alteration is located in exon 3 (coding exon 2) of the FICD gene. This alteration results from a G to A substitution at nucleotide position 571, causing the aspartic acid (D) at amino acid position 191 to be replaced by an asparagine (N). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0086	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.45		Gain of catalytic residue at R193 (P = 0.021);
MVP		0.79
MPC		0.90
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1871998881; hg19: chr12-108912446;