16-31077394-T-G

Variant summary

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

The NM_014699.4(ZNF646):c.1070T>G(p.Leu357Arg) 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: ZNF646 NM_014699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.211

Genes affected

ZNF646 (HGNC:29004): (zinc finger protein 646) 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, DNA-templated. Predicted to be located 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=0.08739349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF646	NM_014699.4	c.1070T>G	p.Leu357Arg	missense_variant	2/3	ENST00000300850.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF646	ENST00000300850.5	c.1070T>G	p.Leu357Arg	missense_variant	2/3	1	NM_014699.4	P2
ZNF646	ENST00000394979.2	c.1070T>G	p.Leu357Arg	missense_variant	1/1			A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

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

Jun 28, 2022

The c.1070T>G (p.L357R) alteration is located in exon 2 (coding exon 1) of the ZNF646 gene. This alteration results from a T to G substitution at nucleotide position 1070, causing the leucine (L) at amino acid position 357 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.083	T;T
Polyphen		1.0	D;.
Vest4		0.23
MutPred		0.43		Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);
MVP		0.43
MPC		0.90
ClinPred		0.35	T
GERP RS		3.7
Varity_R		0.29
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-31088715;