19-55481276-C-T

Position:

• chr19-55481276-C-T

Variant summary

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

The ENST00000598519.2(ZNF628):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF628 ENST00000598519.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

Genes affected

ZNF628 (HGNC:28054): (zinc finger protein 628) Zinc finger proteins (ZNFs), which bind nucleic acids, perform many key functions, the most important of which is regulating transcription. See ZNF91 (MIM 603971) for general information on ZNFs.[supplied by OMIM, Mar 2008]

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=0.06671056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF628	NM_033113.3	c.83C>T	p.Ala28Val	missense_variant	3/3	ENST00000598519.2	NP_149104.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF628	ENST00000598519.2	c.83C>T	p.Ala28Val	missense_variant	3/3	1	NM_033113.3	ENSP00000469591.1
ZNF628	ENST00000591164.1	c.71C>T	p.Ala24Val	missense_variant	2/2	2		ENSP00000465905.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1443674 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 23, 2023

The c.83C>T (p.P28L) alteration is located in exon 3 (coding exon 1) of the ZNF628 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the proline (P) at amino acid position 28 to be replaced by a leucine (L). 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	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0034	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.090	T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.68	.;.;N
REVEL	Benign	0.021
Sift	Uncertain	0.029	.;.;D
Sift4G	Benign	0.31	T;T;T
Vest4		0.16
MVP		0.043
ClinPred		0.084	T
GERP RS		1.1
Varity_R		0.029
gMVP		0.33

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: rs1366213002; hg19: chr19-55992643;