1-90937596-T-A

Variant names:

• chr1-90937596-T-A
• NM_201269.3:c.3577A>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_201269.3(ZNF644):​c.3577A>T​(p.Ile1193Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1193V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZNF644 NM_201269.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13001135).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF644	NM_201269.3	c.3577A>T	p.Ile1193Phe	missense_variant	Exon 4 of 6	ENST00000337393.10	NP_958357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF644	ENST00000337393.10	c.3577A>T	p.Ile1193Phe	missense_variant	Exon 4 of 6	1	NM_201269.3	ENSP00000337008.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461680 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3577A>T (p.I1193F) alteration is located in exon 4 (coding exon 3) of the ZNF644 gene. This alteration results from a A to T substitution at nucleotide position 3577, causing the isoleucine (I) at amino acid position 1193 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.064
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.64	P;P
Vest4		0.46
MutPred		0.18		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.14
MPC		0.52
ClinPred		0.36	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-91403153;