19-51891115-T-C

Position:

• chr19-51891115-T-C

Variant summary

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

The NM_023074.4(ZNF649):​c.1021A>G​(p.Thr341Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF649 NM_023074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

Genes affected

ZNF649 (HGNC:25741): (zinc finger protein 649) Predicted to enable DNA-binding transcription factor activity 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 act upstream of or within negative regulation of transcription, DNA-templated. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF649-AS1 (HGNC:):

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=0.25550327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF649	NM_023074.4	c.1021A>G	p.Thr341Ala	missense_variant	5/5	ENST00000354957.8	NP_075562.2
ZNF649	XM_047439238.1	c.1009A>G	p.Thr337Ala	missense_variant	5/5		XP_047295194.1
ZNF649	XM_047439239.1	c.586A>G	p.Thr196Ala	missense_variant	3/3		XP_047295195.1
ZNF649-AS1	NR_110733.1	n.102+2989T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF649	ENST00000354957.8	c.1021A>G	p.Thr341Ala	missense_variant	5/5	1	NM_023074.4	ENSP00000347043.2
ZNF649	ENST00000600738.5	c.937A>G	p.Thr313Ala	missense_variant	6/6	1		ENSP00000468983.1
ZNF649-AS1	ENST00000600329.1	n.102+2989T>C		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Oct 30, 2023

The c.1021A>G (p.T341A) alteration is located in exon 5 (coding exon 4) of the ZNF649 gene. This alteration results from a A to G substitution at nucleotide position 1021, causing the threonine (T) at amino acid position 341 to be replaced by an alanine (A). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T;T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Benign	0.058
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;.
Vest4		0.19
MutPred		0.48		Loss of phosphorylation at T341 (P = 0.0468);.;
MVP		0.46
MPC		0.59
ClinPred		0.96	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
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: rs948221723; hg19: chr19-52394368;