5-150895617-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052860.4(ZNF300):c.1622G>A(p.Arg541Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,613,258 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: ZNF300 NM_052860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0930

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044618905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF300	NM_052860.4	c.1622G>A	p.Arg541Gln	missense_variant	6/6	ENST00000274599.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF300	ENST00000274599.10	c.1622G>A	p.Arg541Gln	missense_variant	6/6	1	NM_052860.4	P1
ZNF300	ENST00000446148.7	c.1622G>A	p.Arg541Gln	missense_variant	7/7	1		P1
IRGM	ENST00000520549.1	c.*141-4972C>T		intron_variant, NMD_transcript_variant		1
ZNF300	ENST00000427179.5	c.*2437G>A		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000375 AC: 94 AN: 250566 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135422

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000746 AC: 1090 AN: 1461094 Hom.: 1 Cov.: 31 AF XY: 0.000735 AC XY: 534 AN XY: 726790

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000494

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000911

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74404

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.00104

EpiControl AF: 0.000830

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

Dec 31, 2023

The c.1670G>A (p.R557Q) alteration is located in exon 7 (coding exon 5) of the ZNF300 gene. This alteration results from a G to A substitution at nucleotide position 1670, causing the arginine (R) at amino acid position 557 to be replaced by a glutamine (Q). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.53
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.32	T;T;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.045	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.16
MVP		0.41
MPC		0.19
ClinPred		0.046	T
GERP RS		2.7
Varity_R		0.31
gMVP		0.054

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: rs147702441; hg19: chr5-150275179; COSMIC: COSV51033617;