1-90939595-T-G

Variant names:

• chr1-90939595-T-G
• NM_201269.3:c.1759A>C
• ZNF644 p.Ile587Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_201269.3(ZNF644):​c.1759A>C​(p.Ile587Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I587V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF644 NM_201269.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-90939595-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 31108.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03591302).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF644	NM_201269.3	MANE Select	c.1759A>C	p.Ile587Leu	missense	Exon 3 of 6	NP_958357.1	Q9H582-1
	ZNF644	NM_001437612.1		c.1759A>C	p.Ile587Leu	missense	Exon 5 of 9	NP_001424541.1
	ZNF644	NM_001437613.1		c.1759A>C	p.Ile587Leu	missense	Exon 3 of 7	NP_001424542.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF644	ENST00000337393.10	TSL:1 MANE Select	c.1759A>C	p.Ile587Leu	missense	Exon 3 of 6	ENSP00000337008.5	Q9H582-1
	ZNF644	ENST00000347275.9	TSL:1	c.23-21441A>C		intron	N/A	ENSP00000340828.5	Q9H582-3
	ZNF644	ENST00000370440.5	TSL:5	c.1759A>C	p.Ile587Leu	missense	Exon 3 of 6	ENSP00000359469.1	Q9H582-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.41
DANN	Benign	0.57
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.097	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.17
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.033
Sift	Benign	0.60	T
Sift4G	Benign	0.76	T
Varity_R		0.027
gMVP		0.30
Mutation Taster		=24/76	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-91405152;