rs2560306

Positions:

• chr5-122152508-G-A
• chr5-122152508-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_207317.3(ZNF474):​c.518G>A​(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0607 in 1,613,948 control chromosomes in the GnomAD database, including 5,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1880 hom., cov: 32)
  • Exomes 𝑓: 0.055 (3468 hom.)
• Consequence: ZNF474 NM_207317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861

Genes affected

ZNF474 (HGNC:23245): (zinc finger protein 474) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050495863).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF474	NM_207317.3	c.518G>A	p.Arg173His	missense_variant	2/2	ENST00000296600.5	NP_997200.1
ZNF474-AS1	XR_007058915.1	n.272-1905C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF474	ENST00000296600.5	c.518G>A	p.Arg173His	missense_variant	2/2	1	NM_207317.3	ENSP00000296600
	ENST00000504829.1	n.233+2116C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17839 AN: 151978 Hom.: 1875 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0989

GnomAD3 exomes AF: 0.0708 AC: 17735 AN: 250524 Hom.: 1171 AF XY: 0.0668 AC XY: 9044 AN XY: 135376

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.0347

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0616

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0567

GnomAD4 exome AF: 0.0548 AC: 80077 AN: 1461852 Hom.: 3468 Cov.: 31 AF XY: 0.0544 AC XY: 39562 AN XY: 727226

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.0376

Gnomad4 ASJ exome AF: 0.0301

Gnomad4 EAS exome AF: 0.0836

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0987

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0656

GnomAD4 genome AF: 0.118 AC: 17874 AN: 152096 Hom.: 1880 Cov.: 32 AF XY: 0.119 AC XY: 8858 AN XY: 74350

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.0992

Gnomad4 SAS AF: 0.0638

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0574 Hom.: 1002

Bravo AF: 0.122

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.281 AC: 1239

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0747 AC: 9067

Asia WGS AF: 0.0870 AC: 303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	0.89	P
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.33
Sift	Benign	0.036	D
Sift4G	Uncertain	0.038	D
Polyphen		0.15	B
Vest4		0.11
MPC		0.0036
ClinPred		0.093	T
GERP RS		0.80
Varity_R		0.27
gMVP		0.20

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: rs2560306; hg19: chr5-121488203; COSMIC: COSV56945499; COSMIC: COSV56945499;