1-159307784-C-T

Variant names:

• chr1-159307784-C-T
• rs200302228
• NM_001387280.1:c.626C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387280.1(FCER1A):​c.626C>T​(p.Pro209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,611,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: FCER1A NM_001387280.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.776

Genes affected

FCER1A (HGNC:3609): (Fc epsilon receptor Ia) The immunoglobulin epsilon receptor (IgE receptor) is the initiator of the allergic response. When two or more high-affinity IgE receptors are brought together by allergen-bound IgE molecules, mediators such as histamine that are responsible for allergy symptoms are released. This receptor is comprised of an alpha subunit, a beta subunit, and two gamma subunits. The protein encoded by this gene represents the alpha subunit. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19465545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCER1A	NM_001387280.1	c.626C>T	p.Pro209Leu	missense_variant	Exon 5 of 5	ENST00000693622.1	NP_001374209.1
FCER1A	NM_002001.4	c.626C>T	p.Pro209Leu	missense_variant	Exon 7 of 7		NP_001992.1
FCER1A	NM_001387282.1	c.527C>T	p.Pro176Leu	missense_variant	Exon 5 of 5		NP_001374211.1
FCER1A	NM_001387281.1	c.371C>T	p.Pro124Leu	missense_variant	Exon 4 of 4		NP_001374210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCER1A	ENST00000693622.1	c.626C>T	p.Pro209Leu	missense_variant	Exon 5 of 5		NM_001387280.1	ENSP00000509626.1
FCER1A	ENST00000368115.5	c.626C>T	p.Pro209Leu	missense_variant	Exon 6 of 6	1		ENSP00000357097.1
FCER1A	ENST00000368114.1	c.527C>T	p.Pro176Leu	missense_variant	Exon 5 of 5	3		ENSP00000357096.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000797 AC: 20 AN: 251092 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135724

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000528 AC: 77 AN: 1459486 Hom.: 0 Cov.: 30 AF XY: 0.0000606 AC XY: 44 AN XY: 725880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.626C>T (p.P209L) alteration is located in exon 7 (coding exon 5) of the FCER1A gene. This alteration results from a C to T substitution at nucleotide position 626, causing the proline (P) at amino acid position 209 to be replaced by a leucine (L). 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	Benign	0.31
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.20
Sift	Benign	0.050	D;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;.
Vest4		0.44
MVP		0.42
MPC		0.20
ClinPred		0.72	D
GERP RS		4.4
Varity_R		0.11
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs200302228; hg19: chr1-159277574;