3-44594839-A-G

Position:

• chr3-44594839-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173658.4(ZNF660):​c.646A>G​(p.Lys216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF660 NM_173658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

Genes affected

ZNF660 (HGNC:26720): (zinc finger protein 660) This gene encodes a protein that contains multiple C2H2 zinc finger domains, and is located in a cluster of zinc-finger encoding genes on chromosome 3. Naturally-occurring readthrough transcription is observed between this gene and the downstream zinc finger protein 197 gene and is represented by GeneID:110354863. [provided by RefSeq, May 2017]

ZNF660-ZNF197 (HGNC:):

ZNF197 (HGNC:12988): (zinc finger protein 197) This gene product belongs to the zinc finger protein superfamily, members of which are regulatory proteins characterized by nucleic acid-binding zinc finger domains. The encoded protein contains 20 tandemly arrayed C2H2-type zinc fingers, a Kruppel-associated box (KRAB) domain, and a SCAN box. This transcript turns over rapidly and contains 3' UTR AUUUA motifs, which are often a hallmark of rapid turnover. It is overexpressed in some thyroid papillary carcinomas. This gene is located in a cluster of zinc finger genes at 3p21. Naturally-occurring readthrough transcription is observed between this gene and the upstream zinc finger protein 660 gene and is represented by GeneID:110354863. [provided by RefSeq, May 2017]

ZKSCAN7-AS1 (HGNC:53964): (ZKSCAN7 ZNF cluster antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3431945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF660	NM_173658.4	c.646A>G	p.Lys216Glu	missense_variant	3/3	ENST00000322734.2	NP_775929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF660	ENST00000322734.2	c.646A>G	p.Lys216Glu	missense_variant	3/3	2	NM_173658.4	ENSP00000324605.2
ZNF197	ENST00000412641.1	c.-82+8626A>G		intron_variant		2		ENSP00000394713.1
ZKSCAN7-AS1	ENST00000457331.2	n.233-37247T>C		intron_variant		3
ZKSCAN7-AS1	ENST00000685649.2	n.225-33246T>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.646A>G (p.K216E) alteration is located in exon 3 (coding exon 1) of the ZNF660 gene. This alteration results from a A to G substitution at nucleotide position 646, causing the lysine (K) at amino acid position 216 to be replaced by a glutamic acid (E). 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	Pathogenic	0.89
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.38		Loss of methylation at K216 (P = 0.002);
MVP		0.24
MPC		0.097
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.55
gMVP		0.013

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: rs1700558098; hg19: chr3-44636331;