19-51891381-T-C

Variant names:

• chr19-51891381-T-C
• NM_023074.4:c.755A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023074.4(ZNF649):​c.755A>G​(p.His252Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 3.91

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF649	NM_023074.4	c.755A>G	p.His252Arg	missense_variant	Exon 5 of 5	ENST00000354957.8	NP_075562.2
ZNF649	XM_047439238.1	c.743A>G	p.His248Arg	missense_variant	Exon 5 of 5		XP_047295194.1
ZNF649	XM_047439239.1	c.320A>G	p.His107Arg	missense_variant	Exon 3 of 3		XP_047295195.1
ZNF649-AS1	NR_110733.1	n.102+3255T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF649	ENST00000354957.8	c.755A>G	p.His252Arg	missense_variant	Exon 5 of 5	1	NM_023074.4	ENSP00000347043.2
ZNF649	ENST00000600738.5	c.671A>G	p.His224Arg	missense_variant	Exon 6 of 6	1		ENSP00000468983.1
ZNF649-AS1	ENST00000600329.1	n.102+3255T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.755A>G (p.H252R) alteration is located in exon 5 (coding exon 4) of the ZNF649 gene. This alteration results from a A to G substitution at nucleotide position 755, causing the histidine (H) at amino acid position 252 to be replaced by an arginine (R). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.41
MutPred		0.50		Gain of MoRF binding (P = 0.0201);.;
MVP		0.90
MPC		0.75
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.19
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-52394634;