1-149791332-C-T

Variant names:

• chr1-149791332-C-T
• rs145342974
• NM_000566.4:c.940C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000566.4(FCGR1A):​c.940C>T​(p.Arg314Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,444,338 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000015 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR1A NM_000566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 2 publications found

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]

ENSG00000233030 (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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06274304).
• BS2: High Homozygotes in GnomAdExome4 at 3 geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000566.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR1A	NM_000566.4	MANE Select	c.940C>T	p.Arg314Cys	missense	Exon 6 of 6	NP_000557.1	P12314-1
	FCGR1A	NM_001378804.1		c.943C>T	p.Arg315Cys	missense	Exon 6 of 6	NP_001365733.1
	FCGR1A	NM_001378805.1		c.919C>T	p.Arg307Cys	missense	Exon 5 of 5	NP_001365734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR1A	ENST00000369168.5	TSL:1 MANE Select	c.940C>T	p.Arg314Cys	missense	Exon 6 of 6	ENSP00000358165.4	P12314-1
	ENSG00000233030	ENST00000428289.1	TSL:1	n.1063+626G>A		intron	N/A
	FCGR1A	ENST00000964516.1		c.1030C>T	p.Arg344Cys	missense	Exon 7 of 7	ENSP00000634575.1

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145696 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000488 AC: 12 AN: 245996 AF XY: 0.0000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1444338 Hom.: 3 Cov.: 31 AF XY: 0.0000195 AC XY: 14 AN XY: 718646

African (AFR) AF: 0.00 AC: 0 AN: 32508

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25548

East Asian (EAS) AF: 0.000230 AC: 9 AN: 39186

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85322

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00000636 AC: 7 AN: 1100560

Other (OTH) AF: 0.0000336 AC: 2 AN: 59486

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000686 AC: 1 AN: 145696 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 71084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37990

American (AMR) AF: 0.0000676 AC: 1 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 5036

South Asian (SAS) AF: 0.00 AC: 0 AN: 4620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66638

Other (OTH) AF: 0.00 AC: 0 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000501 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.6
DANN	Benign	0.51
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.12	N
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.039
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.0080	B
Vest4		0.067
MutPred		0.48		Loss of MoRF binding (P = 0.0154)
MVP		0.19
ClinPred		0.033	T
GERP RS		1.1
Varity_R		0.080
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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: rs145342974; hg19: chr1-149762888;