19-53164469-C-T

Variant names:

• chr19-53164469-C-T
• rs377630128
• NM_024733.5:c.2021G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024733.5(ZNF665):​c.2021G>A​(p.Arg674Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. R674I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF665 NM_024733.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.11

Genes affected

ZNF665 (HGNC:25885): (zinc finger protein 665) 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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07068333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF665	NM_024733.5	c.2021G>A	p.Arg674Lys	missense_variant	Exon 4 of 4	ENST00000396424.5	NP_079009.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF665	ENST00000396424.5	c.2021G>A	p.Arg674Lys	missense_variant	Exon 4 of 4	2	NM_024733.5	ENSP00000379702.2
ZNF665	ENST00000650736.1	c.2021G>A	p.Arg674Lys	missense_variant	Exon 5 of 5			ENSP00000498600.1
ZNF665	ENST00000600412.1	c.1826G>A	p.Arg609Lys	missense_variant	Exon 2 of 2	5		ENSP00000469154.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000429 AC: 1 AN: 232876 Hom.: 0 AF XY: 0.00000795 AC XY: 1 AN XY: 125796

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: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441870 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715496

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.86
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.44	.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.038
Sift	Benign	0.15	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.0040	B;.
Vest4		0.052
MutPred		0.56		Gain of methylation at R674 (P = 0.043);.;
MVP		0.13
MPC		0.033
ClinPred		0.030	T
GERP RS		-2.1
Varity_R		0.075
gMVP		0.043

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: rs377630128; hg19: chr19-53667722;