1-90937668-G-C

Variant names:

• chr1-90937668-G-C
• rs1651479352
• NM_201269.3:c.3505C>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_201269.3(ZNF644):​c.3505C>G​(p.Leu1169Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF644 NM_201269.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1607444).
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF644	NM_201269.3	c.3505C>G	p.Leu1169Val	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.3505C>G	p.Leu1169Val	missense_variant	Exon 4 of 6	1	NM_201269.3	ENSP00000337008.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3505C>G (p.L1169V) alteration is located in exon 4 (coding exon 3) of the ZNF644 gene. This alteration results from a C to G substitution at nucleotide position 3505, causing the leucine (L) at amino acid position 1169 to be replaced by a valine (V). 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	0.066
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0099	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.084	T;T
Polyphen		0.69	P;P
Vest4		0.26
MutPred		0.15		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.18
MPC		0.72
ClinPred		0.69	D
GERP RS		5.1
Varity_R		0.10
gMVP		0.27

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: rs1651479352; hg19: chr1-91403225;