NM_173658.4:c.197C>T

Variant names:

• chr3-44594390-C-T
• rs1245055182
• NM_173658.4:c.197C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173658.4(ZNF660):​c.197C>T​(p.Thr66Ile) 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 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF660 NM_173658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.739
• Publications: 0 publications found

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)

ZKSCAN7 (HGNC:12955): (zinc finger with KRAB and SCAN domains 7) 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03369856).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173658.4. 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
	ZNF660	NM_173658.4	MANE Select	c.197C>T	p.Thr66Ile	missense	Exon 3 of 3	NP_775929.2	Q6AZW8
	ZNF660-ZNF197	NM_001351732.2		c.-82+8177C>T		intron	N/A	NP_001338661.1
	ZNF660-ZNF197	NM_001351733.2		c.-91+8177C>T		intron	N/A	NP_001338662.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF660	ENST00000322734.2	TSL:2 MANE Select	c.197C>T	p.Thr66Ile	missense	Exon 3 of 3	ENSP00000324605.2	Q6AZW8
	ZNF660	ENST00000853529.1		c.197C>T	p.Thr66Ile	missense	Exon 3 of 3	ENSP00000523588.1
	ZNF660	ENST00000913944.1		c.197C>T	p.Thr66Ile	missense	Exon 3 of 3	ENSP00000584003.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151452 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151452 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73930

African (AFR) AF: 0.00 AC: 0 AN: 41126

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.5
DANN	Benign	0.80
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.59	N
PhyloP100		-0.74
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.064
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0040	B
Vest4		0.096
MutPred		0.34		Loss of disorder (P = 0.0458)
MVP		0.030
MPC		0.054
ClinPred		0.025	T
GERP RS		0.67
Varity_R		0.037
gMVP		0.024
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1245055182; hg19: chr3-44635882;