19-51891159-C-G

Variant names:

• chr19-51891159-C-G
• rs1299965204
• NM_023074.4:c.977G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023074.4(ZNF649):​c.977G>C​(p.Gly326Ala) 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. 15/22 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: ZNF649 NM_023074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.104
• Publications: 0 publications found

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:51285): (ZNF649 antisense RNA 1)

ZNF577 (HGNC:28673): (zinc finger protein 577) 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03925392).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023074.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF649	NM_023074.4	MANE Select	c.977G>C	p.Gly326Ala	missense	Exon 5 of 5	NP_075562.2
	ZNF649-AS1	NR_110733.1		n.102+3033C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF649	ENST00000354957.8	TSL:1 MANE Select	c.977G>C	p.Gly326Ala	missense	Exon 5 of 5	ENSP00000347043.2	Q9BS31
	ZNF649	ENST00000600738.5	TSL:1	c.893G>C	p.Gly298Ala	missense	Exon 6 of 6	ENSP00000468983.1	M0QX90
	ZNF649	ENST00000930182.1		c.1001G>C	p.Gly334Ala	missense	Exon 5 of 5	ENSP00000600241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	18
DANN	Benign	0.66
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.27	N
PhyloP100		-0.10
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.053
Sift	Benign	0.86	T
Sift4G	Benign	1.0	T
Polyphen		0.068	B
Vest4		0.069
MutPred		0.58		Loss of disorder (P = 0.0725)
MVP		0.26
MPC		0.37
ClinPred		0.067	T
GERP RS		-1.5
PromoterAI		-0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.022
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1299965204; hg19: chr19-52394412;