rs74315310

chr1-149784224-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM4 PP5 BS2

The NM_000566.4(FCGR1A):c.274C>T(p.Arg92Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,611,110 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 27)
  • Exomes 𝑓: 0.0060 (42 hom.)
• Consequence: FCGR1A NM_000566.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.368

Genes affected

FCGR1A (HGNC:3613): (Fc gamma receptor Ia) This gene encodes a protein that plays an important role in the immune response. This protein is a high-affinity Fc-gamma receptor. The gene is one of three related gene family members located on chromosome 1. [provided by RefSeq, Jul 2008]

LOC124904411 (HGNC:):

H2BC18 (HGNC:24700): (H2B clustered histone 18) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-dependent histone that is a member of the histone H2B family and is found in a histone cluster on chromosome 1. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM4: Stoplost variant in NM_000566.4 Downstream stopcodon found after 390 codons.
• PP5: Variant 1-149784224-C-T is Pathogenic according to our data. Variant chr1-149784224-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14826.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCGR1A	NM_000566.4	c.274C>T	p.Arg92Ter	stop_gained	3/6	ENST00000369168.5
LOC124904411	XM_047438183.1	c.*577-964G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCGR1A	ENST00000369168.5	c.274C>T	p.Arg92Ter	stop_gained	3/6	1	NM_000566.4	P1
FCGR1A	ENST00000444948.5	c.31+1450C>T		intron_variant		2
H2BC18	ENST00000545683.1	c.378-964G>A		intron_variant		2
H2BC18	ENST00000420462.1	n.76-964G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 588 AN: 151310 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00440

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00410 AC: 1001 AN: 243930 Hom.: 6 AF XY: 0.00436 AC XY: 579 AN XY: 132946

Gnomad AFR exome AF: 0.00128

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00475

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00630

Gnomad OTH exome AF: 0.00439

GnomAD4 exome AF: 0.00603 AC: 8796 AN: 1459686 Hom.: 42 Cov.: 31 AF XY: 0.00601 AC XY: 4361 AN XY: 726152

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00709

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00388 AC: 588 AN: 151424 Hom.: 3 Cov.: 27 AF XY: 0.00354 AC XY: 262 AN XY: 73956

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00439

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.00652

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00469 Hom.: 0

Bravo AF: 0.00407

ESP6500AA AF: 0.00174 AC: 6

ESP6500EA AF: 0.00493 AC: 35

ExAC AF: 0.00401 AC: 478

EpiCase AF: 0.00736

EpiControl AF: 0.00762

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

IGG receptor I, phagocytic, familial deficiency of Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Benign	0.090
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.052	N
MutationTaster	Benign	0.37	A;A;A;A
Vest4		0.51
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs74315310; hg19: chr1-149755780; COSMIC: COSV64985637; COSMIC: COSV64985637;