chr19-51891517-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_023074.4(ZNF649):​c.619G>A​(p.Val207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,102 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. V207L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045743763).

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>A	p.Val207Met	missense	Exon 5 of 5	NP_075562.2
	ZNF649-AS1	NR_110733.1		n.102+3391C>T		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>A	p.Val207Met	missense	Exon 5 of 5	ENSP00000347043.2	Q9BS31
	ZNF649	ENST00000600738.5	TSL:1	c.619G>A	p.Val207Met	missense	Exon 5 of 6	ENSP00000468983.1	M0QX90
	ZNF649	ENST00000930182.1		c.643G>A	p.Val215Met	missense	Exon 5 of 5	ENSP00000600241.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251472 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727242

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000335 AC: 15 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: 0.0000405 AC: 45 AN: 1112006

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74356

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000273

EpiControl AF: 0.000237

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	0.24
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00017	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.027
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.038	B
Vest4		0.10
MutPred		0.30		Gain of disorder (P = 0.0423)
MVP		0.26
MPC		0.27
ClinPred		0.029	T
GERP RS		1.6
Varity_R		0.020
gMVP		0.013
Mutation Taster		=100/0	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: rs755880182; hg19: chr19-52394770;