19-53164913-T-A

Position:

• chr19-53164913-T-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.1577A>T​(p.His526Leu) 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: 33)
• Consequence: ZNF665 NM_024733.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.59

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=0.07823178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF665	NM_024733.5	c.1577A>T	p.His526Leu	missense_variant	4/4	ENST00000396424.5	NP_079009.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF665	ENST00000396424.5	c.1577A>T	p.His526Leu	missense_variant	4/4	2	NM_024733.5	ENSP00000379702.2
ZNF665	ENST00000650736.1	c.1577A>T	p.His526Leu	missense_variant	5/5			ENSP00000498600.1
ZNF665	ENST00000600412.1	c.1382A>T	p.His461Leu	missense_variant	2/2	5		ENSP00000469154.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251198 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.1577A>T (p.H526L) alteration is located in exon 4 (coding exon 3) of the ZNF665 gene. This alteration results from a A to T substitution at nucleotide position 1577, causing the histidine (H) at amino acid position 526 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.43
DANN	Benign	0.72
DEOGEN2	Benign	0.056	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Benign	0.042
Sift	Benign	0.37	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.23	B;.
Vest4		0.12
MutPred		0.31		Loss of disorder (P = 0.0476);.;
MVP		0.12
MPC		0.036
ClinPred		0.12	T
GERP RS		-4.5
Varity_R		0.13
gMVP		0.085

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: rs1224615963; hg19: chr19-53668166;