12-124012361-A-C

Variant names:

• chr12-124012361-A-C
• NM_152437.3:c.217A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152437.3(ZNF664):​c.217A>C​(p.Lys73Gln) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF664 NM_152437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.266

Genes affected

ZNF664 (HGNC:25406): (zinc finger protein 664) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF664-RFLNA (HGNC:):

RFLNA (HGNC:27051): (refilin A) Predicted to enable filamin binding activity. Predicted to be involved in several processes, including actin filament bundle organization; negative regulation of bone mineralization involved in bone maturation; and negative regulation of chondrocyte development. Predicted to be located in cytoplasm. Predicted to be active in actin filament bundle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05085835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF664	NM_152437.3	c.217A>C	p.Lys73Gln	missense_variant	Exon 5 of 5	ENST00000337815.9	NP_689650.1
ZNF664	NM_001204298.2	c.217A>C	p.Lys73Gln	missense_variant	Exon 5 of 5		NP_001191227.1
ZNF664-RFLNA	NM_001204299.3	c.-234+38341A>C		intron_variant	Intron 2 of 4		NP_001191228.1
ZNF664-RFLNA	NM_001347902.2	c.-234+38341A>C		intron_variant	Intron 2 of 4		NP_001334831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF664	ENST00000337815.9	c.217A>C	p.Lys73Gln	missense_variant	Exon 5 of 5	1	NM_152437.3	ENSP00000337320.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217A>C (p.K73Q) alteration is located in exon 5 (coding exon 1) of the ZNF664 gene. This alteration results from a A to C substitution at nucleotide position 217, causing the lysine (K) at amino acid position 73 to be replaced by a glutamine (Q). 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	0.32
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.0054	T;T;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.51	.;.;.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.051	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.050	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.20	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.32	B;B;B;B
Vest4		0.047
MutPred		0.31		Gain of catalytic residue at S69 (P = 0.0107);Gain of catalytic residue at S69 (P = 0.0107);Gain of catalytic residue at S69 (P = 0.0107);Gain of catalytic residue at S69 (P = 0.0107);
MVP		0.030
MPC		1.2
ClinPred		0.17	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.092

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: chr12-124496908;