19-51891641-G-C

Position:

• chr19-51891641-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023074.4(ZNF649):​c.495C>G​(p.Phe165Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ZNF649 NM_023074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.526

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037600994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF649	NM_023074.4	c.495C>G	p.Phe165Leu	missense_variant	5/5	ENST00000354957.8	NP_075562.2
ZNF649	XM_047439238.1	c.483C>G	p.Phe161Leu	missense_variant	5/5		XP_047295194.1
ZNF649	XM_047439239.1	c.60C>G	p.Phe20Leu	missense_variant	3/3		XP_047295195.1
ZNF649-AS1	NR_110733.1	n.102+3515G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF649	ENST00000354957.8	c.495C>G	p.Phe165Leu	missense_variant	5/5	1	NM_023074.4	ENSP00000347043.2
ZNF649	ENST00000600738.5	c.495C>G	p.Phe165Leu	missense_variant	5/6	1		ENSP00000468983.1
ZNF649-AS1	ENST00000600329.1	n.102+3515G>C		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Aug 01, 2024

The c.495C>G (p.F165L) alteration is located in exon 5 (coding exon 4) of the ZNF649 gene. This alteration results from a C to G substitution at nucleotide position 495, causing the phenylalanine (F) at amino acid position 165 to be replaced by a leucine (L). 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	0.48
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.19
DANN	Benign	0.62
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00041	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.68	N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;.
Vest4		0.022
MutPred		0.35		Loss of methylation at K167 (P = 0.0879);Loss of methylation at K167 (P = 0.0879);
MVP		0.33
MPC		0.19
ClinPred		0.054	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.022

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: rs748648005; hg19: chr19-52394894;