Variant 19-51891517-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000354957.8(ZNF649):c.619G>C(p.Val207Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF649
ENST00000354957.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.10

Variant links:

Genes affected

ZNF649 (HGNC:25741): (zinc finger protein 649) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription, DNA-templated. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF649 links:

ZNF649-AS1 (HGNC:):

ZNF649-AS1 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=0.059351504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF649	NM_023074.4 linkuse as main transcript	c.619G>C	p.Val207Leu	missense_variant	5/5	ENST00000354957.8	NP_075562.2	Q9BS31
ZNF649	XM_047439238.1 linkuse as main transcript	c.607G>C	p.Val203Leu	missense_variant	5/5		XP_047295194.1
ZNF649	XM_047439239.1 linkuse as main transcript	c.184G>C	p.Val62Leu	missense_variant	3/3		XP_047295195.1
ZNF649-AS1	NR_110733.1 linkuse as main transcript	n.102+3391C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF649	ENST00000354957.8 linkuse as main transcript	c.619G>C	p.Val207Leu	missense_variant	5/5	1	NM_023074.4	ENSP00000347043.2	Q9BS31
ZNF649	ENST00000600738.5 linkuse as main transcript	c.619G>C	p.Val207Leu	missense_variant	5/6	1		ENSP00000468983.1	M0QX90
ZNF649-AS1	ENST00000600329.1 linkuse as main transcript	n.102+3391C>G		intron_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251472

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Mar 31, 2023

The c.619G>C (p.V207L) alteration is located in exon 5 (coding exon 4) of the ZNF649 gene. This alteration results from a G to C substitution at nucleotide position 619, causing the valine (V) at amino acid position 207 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

0.23

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.4

DANN

Benign

0.74

DEOGEN2

Benign

0.0046

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00055

LIST_S2

Benign

0.35

T;T

M_CAP

Benign

0.00080

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.82

N;.

REVEL

Benign

0.035

Sift

Benign

0.30

T;.

Sift4G

Benign

0.28

T;T

Polyphen

0.0

B;.

Vest4

0.037

MutPred

0.41

Gain of catalytic residue at V207 (P = 0.0096);Gain of catalytic residue at V207 (P = 0.0096);

MVP

0.21

MPC

0.17

ClinPred

0.036

GERP RS

1.6

Varity_R

0.039

gMVP

0.014

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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