rs12117237

Positions:

• chr1-90939235-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000337393.10(ZNF644):​c.2119A>G​(p.Lys707Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,614,010 control chromosomes in the GnomAD database, including 21 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (20 hom.)
• Consequence: ZNF644 ENST00000337393.10 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005277008).
• BP6: Variant 1-90939235-T-C is Benign according to our data. Variant chr1-90939235-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 789149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-90939235-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF644	NM_201269.3	c.2119A>G	p.Lys707Glu	missense_variant	3/6	ENST00000337393.10	NP_958357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF644	ENST00000337393.10	c.2119A>G	p.Lys707Glu	missense_variant	3/6	1	NM_201269.3	ENSP00000337008	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00364 AC: 912 AN: 250860 Hom.: 2 AF XY: 0.00375 AC XY: 509 AN XY: 135734

Gnomad AFR exome AF: 0.000626

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00670

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00421 AC: 6157 AN: 1461770 Hom.: 20 Cov.: 34 AF XY: 0.00419 AC XY: 3048 AN XY: 727180

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00388

Gnomad4 FIN exome AF: 0.00568

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74450

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.00493

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00420 Hom.: 2

Bravo AF: 0.00267

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00389 AC: 472

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2018	- -

ZNF644-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	.;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.63	N;N;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.46	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.045	D;D;.
Sift4G	Benign	0.086	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.14
MVP		0.19
MPC		0.33
ClinPred		0.011	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.43

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

Other links and lift over

dbSNP: rs12117237; hg19: chr1-91404792;