19-56441991-C-A

Variant names:

• chr19-56441991-C-A
• rs1048495994
• NM_001321356.2:c.1004G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001321356.2(ZNF667):​c.1004G>T​(p.Cys335Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C335Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF667 NM_001321356.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• Publications: 0 publications found

Genes affected

ZNF667 (HGNC:28854): (zinc finger protein 667) Predicted to enable DNA-binding transcription factor activity 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321356.2. 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
	ZNF667	NM_001321356.2	MANE Select	c.1004G>T	p.Cys335Phe	missense	Exon 7 of 7	NP_001308285.1	Q5HYK9
	ZNF667	NM_022103.4		c.1004G>T	p.Cys335Phe	missense	Exon 5 of 5	NP_071386.3
	ZNF667	NM_001321355.2		c.833G>T	p.Cys278Phe	missense	Exon 6 of 6	NP_001308284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF667	ENST00000504904.8	TSL:2 MANE Select	c.1004G>T	p.Cys335Phe	missense	Exon 7 of 7	ENSP00000439402.1	Q5HYK9
	ZNF667	ENST00000292069.10	TSL:1	c.1004G>T	p.Cys335Phe	missense	Exon 5 of 5	ENSP00000292069.5	Q5HYK9
	ZNF667	ENST00000909113.1		c.1004G>T	p.Cys335Phe	missense	Exon 5 of 5	ENSP00000579172.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111908

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.86
MPC		0.66
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.32
Mutation Taster		=58/42	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: rs1048495994; hg19: chr19-56953360;