rs12460170

Positions:

• chr19-53166239-A-G
• chr19-53166239-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024733.5(ZNF665):​c.251T>C​(p.Val84Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,613,672 control chromosomes in the GnomAD database, including 305,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (22946 hom., cov: 32)
  • Exomes 𝑓: 0.62 (282136 hom.)
• Consequence: ZNF665 NM_024733.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1620522E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF665	NM_024733.5	c.251T>C	p.Val84Ala	missense_variant	4/4	ENST00000396424.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF665	ENST00000396424.5	c.251T>C	p.Val84Ala	missense_variant	4/4	2	NM_024733.5	P1
ZNF665	ENST00000650736.1	c.251T>C	p.Val84Ala	missense_variant	5/5			P1
ZNF665	ENST00000600412.1	c.56T>C	p.Val19Ala	missense_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78436 AN: 151966 Hom.: 22934 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.518

GnomAD3 exomes AF: 0.624 AC: 155501 AN: 249198 Hom.: 50581 AF XY: 0.629 AC XY: 85090 AN XY: 135184

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.731

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.663

Gnomad SAS exome AF: 0.715

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.616 AC: 900457 AN: 1461588 Hom.: 282136 Cov.: 59 AF XY: 0.620 AC XY: 450496 AN XY: 727062

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.718

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.715

Gnomad4 FIN exome AF: 0.674

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.589

GnomAD4 genome AF: 0.516 AC: 78477 AN: 152084 Hom.: 22946 Cov.: 32 AF XY: 0.524 AC XY: 38942 AN XY: 74324

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.655

Gnomad4 SAS AF: 0.715

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.520

Alfa AF: 0.591 Hom.: 55516

Bravo AF: 0.496

TwinsUK AF: 0.611 AC: 2266

ALSPAC AF: 0.603 AC: 2323

ESP6500AA AF: 0.224 AC: 870

ESP6500EA AF: 0.607 AC: 5044

ExAC AF: 0.617 AC: 74565

EpiCase AF: 0.606

EpiControl AF: 0.592

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.21
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00096	N
LIST_S2	Benign	0.0096	T;T
MetaRNN	Benign	0.0000022	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.5	N;.
REVEL	Benign	0.032
Sift	Benign	0.33	T;.
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;.
Vest4		0.023
MPC		0.032
ClinPred		0.0065	T
GERP RS		0.40
Varity_R		0.083
gMVP		0.023

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: rs12460170; hg19: chr19-53669492; COSMIC: COSV67215082; COSMIC: COSV67215082;