chr5-122152178-C-A

Variant names:

• chr5-122152178-C-A
• rs761268305
• NM_207317.3:c.188C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207317.3(ZNF474):​c.188C>A​(p.Pro63His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P63A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ZNF474 NM_207317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

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

ENSG00000250803 (HGNC:53564): (zinc finger protein 475)

ENSG00000247311 (HGNC:):

ZNF474-AS1 (HGNC:41019): (ZNF474 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39440197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF474	NM_207317.3	c.188C>A	p.Pro63His	missense_variant	Exon 2 of 2	ENST00000296600.5	NP_997200.1
ZNF474-AS1	XR_007058915.1	n.272-1575G>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF474	ENST00000296600.5	c.188C>A	p.Pro63His	missense_variant	Exon 2 of 2	1	NM_207317.3	ENSP00000296600.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.188C>A (p.P63H) alteration is located in exon 2 (coding exon 1) of the ZNF474 gene. This alteration results from a C to A substitution at nucleotide position 188, causing the proline (P) at amino acid position 63 to be replaced by a histidine (H). 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	0.37
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.26		Loss of glycosylation at P63 (P = 0.0367);Loss of glycosylation at P63 (P = 0.0367);
MVP		0.45
MPC		0.015
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.085

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: rs761268305; hg19: chr5-121487873;