dbSNP rs59922637: ZNF644:p.Thr870Ala (chr1-90938746-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201269.3(ZNF644):c.2608A>G(p.Thr870Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,613,938 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 45 hom. )

Consequence

ZNF644
NM_201269.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.88

Publications

2 publications found

Variant links:

Genes affected

ZNF644 (HGNC:29222): (zinc finger protein 644) The protein encoded by this gene is a zinc finger transcription factor that may play a role in eye development. Defects in this gene have been associated with high myopia. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ZNF644 Gene-Disease associations (from GenCC):

myopia 21, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics

ZNF644 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004046917).

BP6

Variant 1-90938746-T-C is Benign according to our data. Variant chr1-90938746-T-C is described in ClinVar as Benign. ClinVar VariationId is 780246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1924/152238) while in subpopulation AFR AF = 0.0438 (1819/41546). AF 95% confidence interval is 0.0421. There are 39 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1924 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201269.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZNF644	NM_201269.3	MANE Select	c.2608A>G	p.Thr870Ala	missense	Exon 3 of 6	NP_958357.1
ZNF644	NM_001437612.1		c.2608A>G	p.Thr870Ala	missense	Exon 5 of 9	NP_001424541.1
ZNF644	NM_001437613.1		c.2608A>G	p.Thr870Ala	missense	Exon 3 of 7	NP_001424542.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZNF644	ENST00000337393.10	TSL:1 MANE Select	c.2608A>G	p.Thr870Ala	missense	Exon 3 of 6	ENSP00000337008.5
ZNF644	ENST00000347275.9	TSL:1	c.23-20592A>G		intron	N/A	ENSP00000340828.5
ZNF644	ENST00000370440.5	TSL:5	c.2608A>G	p.Thr870Ala	missense	Exon 3 of 6	ENSP00000359469.1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1917

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00336

AC:

842

AN:

250690

AF XY:

0.00242

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00132

AC:

1927

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

797

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0466

AC:

1561

AN:

33474

American (AMR)

AF:

0.00239

AC:

107

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000773

AC:

AN:

1111916

Other (OTH)

AF:

0.00263

AC:

159

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

121

242

362

483

604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0126

AC:

1924

AN:

152238

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

917

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0438

AC:

1819

AN:

41546

American (AMR)

AF:

0.00497

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67994

Other (OTH)

AF:

0.00996

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

183

275

366

458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00461

Hom.:

Bravo

AF:

0.0148

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0397

AC:

175

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00391

AC:

475

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

Eigen

Benign

-0.11

Eigen_PC

Benign

0.013

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.97

PhyloP100

3.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.50

REVEL

Benign

0.16

Sift

Uncertain

0.0030

Sift4G

Benign

0.30

Polyphen

0.45

Vest4

0.13

MVP

0.30

MPC

0.38

ClinPred

0.048

GERP RS

3.1

Varity_R

0.050

gMVP

0.32

Mutation Taster

=89/11

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over