rs755880182

Variant names:

• chr19-51891517-C-G
• rs755880182
• NM_023074.4:c.619G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-51891517-C-G
• chr19-51891517-C-T

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.619G>C​(p.Val207Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V207M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF649 NM_023074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• Publications: 2 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)

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=0.059351504).

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.619G>C	p.Val207Leu	missense	Exon 5 of 5	NP_075562.2
	ZNF649-AS1	NR_110733.1		n.102+3391C>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.619G>C	p.Val207Leu	missense	Exon 5 of 5	ENSP00000347043.2	Q9BS31
	ZNF649	ENST00000600738.5	TSL:1	c.619G>C	p.Val207Leu	missense	Exon 5 of 6	ENSP00000468983.1	M0QX90
	ZNF649	ENST00000930182.1		c.643G>C	p.Val215Leu	missense	Exon 5 of 5	ENSP00000600241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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	0.23
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.4
DANN	Benign	0.74
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.00080	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.035
Sift	Benign	0.30	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.41		Gain of catalytic residue at V207 (P = 0.0096)
MVP		0.21
MPC		0.17
ClinPred		0.036	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.014
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs755880182; hg19: chr19-52394770;