NM_052860.4:c.1427G>A

Variant names:

• chr5-150895812-C-T
• rs554976762
• NM_052860.4:c.1427G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052860.4(ZNF300):​c.1427G>A​(p.Arg476His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ZNF300 NM_052860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.50
• Publications: 2 publications found

Genes affected

ZNF300 (HGNC:13091): (zinc finger protein 300) The protein encoded by this gene is a C2H2-type zinc finger DNA binding protein and likely transcriptional regulator. The function of this protein is not yet known. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

IRGM (HGNC:29597): (immunity related GTPase M) This gene encodes a member of the p47 immunity-related GTPase family. The encoded protein may play a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens. Polymorphisms that affect the normal expression of this gene are associated with a susceptibility to Crohn's disease and tuberculosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07777721).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052860.4. 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
	ZNF300	NM_052860.4	MANE Select	c.1427G>A	p.Arg476His	missense	Exon 6 of 6	NP_443092.1	Q96RE9-1
	ZNF300	NM_001172831.3		c.1475G>A	p.Arg492His	missense	Exon 7 of 7	NP_001166302.1	Q96RE9-3
	ZNF300	NM_001172832.3		c.1319G>A	p.Arg440His	missense	Exon 5 of 5	NP_001166303.1	Q96RE9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF300	ENST00000274599.10	TSL:1 MANE Select	c.1427G>A	p.Arg476His	missense	Exon 6 of 6	ENSP00000274599.5	Q96RE9-1
	ZNF300	ENST00000446148.7	TSL:1	c.1427G>A	p.Arg476His	missense	Exon 7 of 7	ENSP00000397178.3	Q96RE9-1
	IRGM	ENST00000520549.1	TSL:1	n.*141-4777C>T		intron	N/A	ENSP00000429819.1	A0A9H4B933

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151586 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461368 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726984

African (AFR) AF: 0.0000598 AC: 2 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151586 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74012

African (AFR) AF: 0.000121 AC: 5 AN: 41272

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000264

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	Uncertain	0.51
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.000040	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PhyloP100		-1.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.036
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Polyphen		0.12	B
Vest4		0.082
MutPred		0.59		Loss of MoRF binding (P = 0.0145)
MVP		0.16
MPC		0.19
ClinPred		0.085	T
GERP RS		0.15
Varity_R		0.065
gMVP		0.092
Mutation Taster		=99/1	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: rs554976762; hg19: chr5-150275374; COSMIC: COSV51061371;