Variant 1-182056704-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000339948.3(ZNF648):c.1307C>T(p.Ser436Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,596,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. S436Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

ZNF648
ENST00000339948.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.307

Variant links:

Genes affected

ZNF648 (HGNC:18190): (zinc finger protein 648) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF648 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.005179763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF648	NM_001009992.1 linkuse as main transcript	c.1307C>T	p.Ser436Phe	missense_variant	2/2	ENST00000339948.3	NP_001009992.1	Q5T619
ZNF648	XM_024453260.2 linkuse as main transcript	c.1307C>T	p.Ser436Phe	missense_variant	3/3		XP_024309028.1
ZNF648	XM_047445722.1 linkuse as main transcript	c.1307C>T	p.Ser436Phe	missense_variant	4/4		XP_047301678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF648	ENST00000339948.3 linkuse as main transcript	c.1307C>T	p.Ser436Phe	missense_variant	2/2	1	NM_001009992.1	ENSP00000344129.3		Q5T619
ZNF648	ENST00000673963.1 linkuse as main transcript	c.752C>T	p.Ser251Phe	missense_variant	2/2			ENSP00000501285.1		A0A669KBK7

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000620

AC:

134

AN:

216202

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

116748

show subpopulations

Gnomad AFR exome

AF:

0.000379

Gnomad AMR exome

AF:

0.000808

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000482

Gnomad NFE exome

AF:

0.000902

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.000663

AC:

957

AN:

1444472

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

437

AN XY:

716990

show subpopulations

Gnomad4 AFR exome

AF:

0.000212

Gnomad4 AMR exome

AF:

0.000883

Gnomad4 ASJ exome

AF:

0.0000775

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000844

Gnomad4 NFE exome

AF:

0.000752

Gnomad4 OTH exome

AF:

0.000603

GnomAD4 genome

AF:

0.000584

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000711

Hom.:

Bravo

AF:

0.000771

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000644

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.1307C>T (p.S436F) alteration is located in exon 2 (coding exon 1) of the ZNF648 gene. This alteration results from a C to T substitution at nucleotide position 1307, causing the serine (S) at amino acid position 436 to be replaced by a phenylalanine (F). 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

0.24

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.5

DANN

Benign

0.93

DEOGEN2

Benign

0.0052

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.69

M_CAP

Benign

0.00085

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.86

REVEL

Benign

0.014

Sift

Benign

0.52

Sift4G

Benign

0.72

Polyphen

0.0010

Vest4

0.12

MVP

0.095

MPC

0.42

ClinPred

0.0022

GERP RS

0.41

Varity_R

0.047

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over