3-44594855-A-C

Variant names:

• chr3-44594855-A-C
• rs1318076814
• NM_173658.4:c.662A>C

Variant summary

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

The NM_173658.4(ZNF660):​c.662A>C​(p.Asp221Ala) 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: 32)
• Consequence: ZNF660 NM_173658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.24

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 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=0.03962943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF660	NM_173658.4	c.662A>C	p.Asp221Ala	missense_variant	Exon 3 of 3	ENST00000322734.2	NP_775929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF660	ENST00000322734.2	c.662A>C	p.Asp221Ala	missense_variant	Exon 3 of 3	2	NM_173658.4	ENSP00000324605.2
ZNF197	ENST00000412641.1	c.-82+8642A>C		intron_variant	Intron 2 of 2	2		ENSP00000394713.1
ZKSCAN7-AS1	ENST00000457331.2	n.233-37263T>G		intron_variant	Intron 2 of 2	3
ZKSCAN7-AS1	ENST00000685649.2	n.225-33262T>G		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251300 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662A>C (p.D221A) alteration is located in exon 3 (coding exon 1) of the ZNF660 gene. This alteration results from a A to C substitution at nucleotide position 662, causing the aspartic acid (D) at amino acid position 221 to be replaced by an alanine (A). 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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.071
Sift	Benign	0.14	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0	B
Vest4		0.097
MutPred		0.24		Loss of glycosylation at K216 (P = 0.0276);
MVP		0.030
MPC		0.076
ClinPred		0.028	T
GERP RS		1.9
Varity_R		0.077
gMVP		0.047

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: rs1318076814; hg19: chr3-44636347;