rs60262072

chr1-90939658-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_201269.3(ZNF644):c.1696A>T(p.Thr566Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,982 control chromosomes in the GnomAD database, including 81 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 (★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: ZNF644 NM_201269.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002323389).
• BP6: Variant 1-90939658-T-A is Benign according to our data. Variant chr1-90939658-T-A is described in ClinVar as [Benign]. Clinvar id is 780247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1896/152186) while in subpopulation AFR AF= 0.0432 (1792/41520). AF 95% confidence interval is 0.0415. There are 37 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1889 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF644	NM_201269.3	c.1696A>T	p.Thr566Ser	missense_variant	3/6	ENST00000337393.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF644	ENST00000337393.10	c.1696A>T	p.Thr566Ser	missense_variant	3/6	1	NM_201269.3	P1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152068 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

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: 0.0100

GnomAD3 exomes AF: 0.00334 AC: 836 AN: 250344 Hom.: 22 AF XY: 0.00241 AC XY: 326 AN XY: 135294

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00130 AC: 1900 AN: 1461796 Hom.: 44 Cov.: 34 AF XY: 0.00108 AC XY: 785 AN XY: 727200

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.0125 AC: 1896 AN: 152186 Hom.: 37 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74414

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00212 Hom.: 3

Bravo AF: 0.0147

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00391 AC: 475

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	16
Dann	Benign	0.89
DEOGEN2	Benign	0.0056	T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.22	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.26	T;T;.
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.12
MVP		0.37
MPC		0.21
ClinPred		0.015	T
GERP RS		4.6
Varity_R		0.056
gMVP		0.23

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: rs60262072; hg19: chr1-91405215;