chr1-90939235-T-C

Variant names:

• chr1-90939235-T-C
• rs12117237
• NM_201269.3:c.2119A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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:4
• Conservation: PhyloP100: 2.09
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 789149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 492 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000337393.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF644	NM_201269.3	MANE Select	c.2119A>G	p.Lys707Glu	missense	Exon 3 of 6	NP_958357.1
	ZNF644	NM_001437612.1		c.2119A>G	p.Lys707Glu	missense	Exon 5 of 9	NP_001424541.1
	ZNF644	NM_001437613.1		c.2119A>G	p.Lys707Glu	missense	Exon 3 of 7	NP_001424542.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF644	ENST00000337393.10	TSL:1 MANE Select	c.2119A>G	p.Lys707Glu	missense	Exon 3 of 6	ENSP00000337008.5
	ZNF644	ENST00000347275.9	TSL:1	c.23-21081A>G		intron	N/A	ENSP00000340828.5
	ZNF644	ENST00000370440.5	TSL:5	c.2119A>G	p.Lys707Glu	missense	Exon 3 of 6	ENSP00000359469.1

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

GnomAD2 exomes AF: 0.00364 AC: 912 AN: 250860 AF XY: 0.00375

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 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

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00388 AC: 335 AN: 86250

European-Finnish (FIN) AF: 0.00568 AC: 303 AN: 53392

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00457 AC: 5083 AN: 1111948

Other (OTH) AF: 0.00426 AC: 257 AN: 60392

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

African (AFR) AF: 0.000986 AC: 41 AN: 41562

American (AMR) AF: 0.00157 AC: 24 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00493 AC: 335 AN: 67978

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00414 Hom.: 5

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ZNF644-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.63	N
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.16
Sift	Benign	0.045	D
Sift4G	Benign	0.086	T
Polyphen		0.0040	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs12117237; hg19: chr1-91404792;