Genetic Variant ZNF646:p.Glu327Gly (chr16-31077304-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014699.4(ZNF646):c.980A>G(p.Glu327Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,612,972 control chromosomes in the GnomAD database, including 125,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 9906 hom., cov: 33)

Exomes 𝑓: 0.38 ( 115476 hom. )

Consequence

ZNF646
NM_014699.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.126

Publications

51 publications found

Variant links:

Genes affected

ZNF646 (HGNC:29004): (zinc finger protein 646) 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]

ZNF646 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.00967E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF646	NM_014699.4 link	c.980A>G	p.Glu327Gly	missense_variant	Exon 2 of 3	ENST00000300850.5	NP_055514.3	O15015-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF646	ENST00000300850.5 link	c.980A>G	p.Glu327Gly	missense_variant	Exon 2 of 3	1	NM_014699.4	ENSP00000300850.5		O15015-2
ZNF646	ENST00000394979.2 link	c.980A>G	p.Glu327Gly	missense_variant	Exon 1 of 1	6		ENSP00000378429.2		O15015-1

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47383

AN:

152058

Hom.:

9905

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0739

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.890

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.390

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.378

Gnomad OTH

AF:

0.382

GnomAD2 exomes

AF:

0.395

AC:

98241

AN:

248600

AF XY:

0.386

show subpopulations

Gnomad AFR exome

AF:

0.0664

Gnomad AMR exome

AF:

0.456

Gnomad ASJ exome

AF:

0.488

Gnomad EAS exome

AF:

0.893

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.394

Gnomad OTH exome

AF:

0.406

GnomAD4 exome

AF:

0.380

AC:

555213

AN:

1460796

Hom.:

115476

Cov.:

AF XY:

0.376

AC XY:

273013

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.0645

AC:

2159

AN:

33468

American (AMR)

AF:

0.454

AC:

20230

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12802

AN:

26130

East Asian (EAS)

AF:

0.903

AC:

35805

AN:

39632

South Asian (SAS)

AF:

0.185

AC:

15955

AN:

86216

European-Finnish (FIN)

AF:

0.390

AC:

20737

AN:

53150

Middle Eastern (MID)

AF:

0.489

AC:

2819

AN:

5766

European-Non Finnish (NFE)

AF:

0.379

AC:

421219

AN:

1111538

Other (OTH)

AF:

0.389

AC:

23487

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

22965

45930

68896

91861

114826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.311

AC:

47383

AN:

152176

Hom.:

9906

Cov.:

AF XY:

0.314

AC XY:

23364

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0738

AC:

3065

AN:

41558

American (AMR)

AF:

0.389

AC:

5942

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1732

AN:

3470

East Asian (EAS)

AF:

0.891

AC:

4596

AN:

5160

South Asian (SAS)

AF:

0.178

AC:

857

AN:

4818

European-Finnish (FIN)

AF:

0.390

AC:

4132

AN:

10584

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.378

AC:

25701

AN:

67976

Other (OTH)

AF:

0.380

AC:

803

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1476

2953

4429

5906

7382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.387

Hom.:

22096

Bravo

AF:

0.314

TwinsUK

AF:

0.371

AC:

1374

ALSPAC

AF:

0.367

AC:

1416

ESP6500AA

AF:

0.0892

AC:

392

ESP6500EA

AF:

0.403

AC:

3462

ExAC

AF:

0.381

AC:

46216

Asia WGS

AF:

0.456

AC:

1589

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

7.0e-7

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.90

L;L

PhyloP100

0.13

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.14

Sift

Benign

0.12

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.019

B;.

Vest4

0.097

MPC

0.39

ClinPred

0.0048

GERP RS

4.2

Varity_R

0.037

gMVP

0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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16-31077304-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over