5-150896479-G-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.760C>A(p.Gln254Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ZNF300 NM_052860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.595

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=0.033648074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF300	NM_052860.4	c.760C>A	p.Gln254Lys	missense_variant	6/6	ENST00000274599.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF300	ENST00000274599.10	c.760C>A	p.Gln254Lys	missense_variant	6/6	1	NM_052860.4	P1
ZNF300	ENST00000446148.7	c.760C>A	p.Gln254Lys	missense_variant	7/7	1		P1
IRGM	ENST00000520549.1	c.*141-4110G>T		intron_variant, NMD_transcript_variant		1
ZNF300	ENST00000427179.5	c.*1575C>A		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250206 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461210 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.808C>A (p.Q270K) alteration is located in exon 7 (coding exon 5) of the ZNF300 gene. This alteration results from a C to A substitution at nucleotide position 808, causing the glutamine (Q) at amino acid position 270 to be replaced by a lysine (K). 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	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.90
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.00013	N
LIST_S2	Benign	0.017	T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.086	.;B;.;.
Vest4		0.20
MutPred		0.57		.;Gain of methylation at Q254 (P = 0.0087);.;Gain of methylation at Q254 (P = 0.0087);
MVP		0.24
MPC		0.31
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.13
gMVP		0.060

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: rs745625061; hg19: chr5-150276041;