dbSNP rs17131242: ZNF644:p.Met556Val (chr1-90939688-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201269.3(ZNF644):c.1666A>G(p.Met556Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,614,022 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.013 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 45 hom. )

Consequence

ZNF644
NM_201269.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.376

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017351508).

BP6

Variant 1-90939688-T-C is Benign according to our data. Variant chr1-90939688-T-C is described in ClinVar as [Benign]. Clinvar id is 780248.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 = 0.0127 (1930/152262) while in subpopulation AFR AF= 0.0438 (1819/41574). AF 95% confidence interval is 0.0421. There are 39 homozygotes in gnomad4. There are 921 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1930 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF644	NM_201269.3 link	c.1666A>G	p.Met556Val	missense_variant	Exon 3 of 6	ENST00000337393.10	NP_958357.1	Q9H582-1A7E234

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF644	ENST00000337393.10 link	c.1666A>G	p.Met556Val	missense_variant	Exon 3 of 6	1	NM_201269.3	ENSP00000337008.5		Q9H582-1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1923

AN:

152144

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:

0.000772

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.00343

AC:

858

AN:

250042

Hom.:

AF XY:

0.00249

AC XY:

337

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000599

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000977

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00135

AC:

1978

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

819

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0466

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.00270

GnomAD4 genome

AF:

0.0127

AC:

1930

AN:

152262

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0438

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00996

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.0148

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0399

AC:

176

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.00375

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0080

DANN

Benign

0.20

DEOGEN2

Benign

0.0035

T;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.48

.;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N;.

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.070

N;N;.

REVEL

Benign

0.012

Sift

Benign

0.82

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.097

MVP

0.12

MPC

0.24

ClinPred

0.00082

GERP RS

-4.2

Varity_R

0.027

gMVP

0.34

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