3-40529376-C-T

Position:

• chr3-40529376-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000339296.10(ZNF621):​c.82C>T​(p.Leu28Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF621 ENST00000339296.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

ZNF621 (HGNC:24787): (zinc finger protein 621) 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF621 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF621	NM_198484.5	c.82C>T	p.Leu28Phe	missense_variant	3/5	ENST00000339296.10	NP_940886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF621	ENST00000339296.10	c.82C>T	p.Leu28Phe	missense_variant	3/5	1	NM_198484.5	ENSP00000340841.5

Frequencies

GnomAD3 genomes Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.82C>T (p.L28F) alteration is located in exon 3 (coding exon 2) of the ZNF621 gene. This alteration results from a C to T substitution at nucleotide position 82, causing the leucine (L) at amino acid position 28 to be replaced by a phenylalanine (F). 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;T;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	4.2	H;H;H;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.58
MutPred		0.85		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.50
MPC		0.76
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.43
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-40570867;