19-51891616-T-C

Variant names:

• chr19-51891616-T-C
• rs376994779
• NM_023074.4:c.520A>G

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.520A>G​(p.Ile174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,894 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I174L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ZNF649 NM_023074.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• 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)

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=0.06406212).

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.520A>G	p.Ile174Val	missense	Exon 5 of 5	NP_075562.2
	ZNF649-AS1	NR_110733.1		n.102+3490T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF649	ENST00000354957.8	TSL:1 MANE Select	c.520A>G	p.Ile174Val	missense	Exon 5 of 5	ENSP00000347043.2	Q9BS31
	ZNF649	ENST00000600738.5	TSL:1	c.520A>G	p.Ile174Val	missense	Exon 5 of 6	ENSP00000468983.1	M0QX90
	ZNF649	ENST00000930182.1		c.544A>G	p.Ile182Val	missense	Exon 5 of 5	ENSP00000600241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

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: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000180 AC: 20 AN: 1112012

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.83
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.00083	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-0.16
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.026
Sift	Benign	0.50	T
Sift4G	Benign	0.43	T
Polyphen		0.032	B
Vest4		0.070
MutPred		0.36		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.23
MPC		0.16
ClinPred		0.055	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.0096
Mutation Taster		=97/3	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: rs376994779; hg19: chr19-52394869;